DE60317109T2 - ESTRIENOÄ3,2-BÜ / Ä3,4-CÜPYRROLE DERIVATIVE AS MODULATORS OF THE ÖSTROGEN RECEPTOR - Google Patents

Abstract

The present invention is directed to novel estrieno[3,2-b]/[3,4-c]pyrrole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and diseases mediated by an estrogen receptor.

Description

FIELD OF THE INVENTION

The present invention is directed to novel estrato [3,2-b] / [3,4-c] pyrrole derivatives, pharmaceutical compositions containing them, and their Use in the treatment or prevention of disorders and Diseases mediated by an estrogen receptor, such as Hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular Diseases, hormone-sensitive cancers and hyperplasia (in tissues, including Breast, uterine lining, cervix in women and the prostate in men), endometriosis, uterine fibroids, osteoarthritis; and as a contraceptive, either alone or in combination with a progestogen or progestogen antagonist. The compounds of the invention are selective estrogen receptor modulators.

BACKGROUND OF THE INVENTION

estrogens are a group of female hormones essential for the reproductive process and development the uterus, breasts and other physical changes, which are related to puberty. estrogens have an effect on different tissues throughout the body Woman, not just those involved in the reproduction process are, such as uterus, breasts and external genitals, but also tissues in the central nervous system, bones, the liver, Skin and urinary tract. The ovaries produce most of the Estrogens in the body by women.

endogenous Estrogens, such as 17b-estradiol and estrone, play a central role Role in the development and maintenance of female genitalia, mammary glands and other sexual characteristics. In addition to her role as a female Sex hormone, estrogens are involved in growth and function a number of other tissues, such as the cardiovascular system, the central nervous system and the skeleton, both in women and also men. The significance of estrogens in the development of the female Reproduction system led To develop a variety of compounds with the estrogen receptors Interact, such as contraceptives and agents for the treatment of breast cancer. Recently Intensive efforts have been made on the selective estrogen receptor modulators focused on the treatment and prevention of postmenopausal conditions, such as osteoporosis, coronary artery disease, depression and Alzheimer's disease.

menopause is defined as the permanent cessation of menstrual bleeding due to loss of ovarian follicular function and almost cessation the estrogen production. The menopausal transition in the middle of life is characterized by a reduction of estrogen, both short-term as well as long-term symptoms with the vasomotor, genitourinary, cardiovascular, skeletal and central nervous systems, such as hot flashes, Urogenital atrophy, elevated Risk cardiovascular Illness, osteoporosis, cognitive and psychological impairment, including an increased risk for cognitive disorders and Alzheimer's disease (AD).

Seventyfive Percent of all women experience an occurrence of vasomotor symptoms associated with the onset of menopause, such as about body sweating and hot flashes. These complaints can take several years before the Menopause can and does start for some women for more than 10 years either relatively constant or as sudden Continue attacks without a definable, causal reason.

With urogenital symptoms related to the onset of menopause, which affect the vagina, close a sense of dryness, burning, Itching, pain during of intercourse, superficial Bleeding and discharge, together with atrophy and stenosis, a. Symptoms affecting the urinary tract to close a burning sensation while of urinating, frequent Urinary urgency, recurrent urinary tract infections and urinary incontinence one. It has been reported that these symptoms are up to 50% All women near the time of menopause occur and enter few years after menopause more often are. If left untreated, the problems can be permanent become.

Heart attack and stroke are important causes of morbidity and mortality among older women. Morbidity in women with these diseases increases rapidly after the menopause. Women undergoing premature menopause are at greater risk for coronary artery disease than menstruating women of the same age. The presence of serum estrogen has a positive effect on serum lipids. The hormone promotes the Vasodilation of blood vessels and enhances the formation of new blood vessels. Reduction of serum estrogen levels in postmenopausal women leads to adverse cardiovascular effects. In addition, it is argued that differences in the ability of the blood to coagulate might account for the observed difference in the incidence of pre- and post-menopausal heart disease.

The Skeleton undergoes a continuous process of bone degeneration and regeneration in a carefully regulated interaction among the bone cells. These cells are directly influenced by estrogen. Estrogen deficiency leads to a Loss of bone structure and a decrease in bone strength. Rapid loss of bone mass during the year immediately in connection to the menopause leads to postmenopausal osteoporosis and increased risk of breakage.

Estrogen deficiency is also one of the reasons for the degenerative changes in the central nervous system and can cause Alzheimer's disease and decline in the Lead cognition. recent Evidence links estrogen, menopause and cognition Near. In particular, it has been reported that estrogen replacement therapy and the use of estrogen in women's development of AD prevent and improve cognitive function.

Hormone replacement therapy (HRT) - in particular Estrogen replacement therapy (ERT) - is usually prescribed to treat the medical problems associated with menopause are linked, and also to help, osteoporosis and primary cardiovascular complications (such as coronary artery disease) in both a preventive as well as therapeutic way to prevent. As such, HRT becomes as a medical therapy to prolong the average Lifespan of postmenopausal women and providing a better quality of life considered.

ERT Effectively relieves climacteric symptoms and urogenital symptoms and has significant advantages in prevention and treatment of heart disease in postmenopausal women. clinical Reports have shown that ERT heart failure rates and mortality rates in populations receiving ERT decreased compared to similar populations received no ERT. ERT, which is initiated soon after menopause, can also help for to preserve the bone mass for several years. Have controlled investigations demonstrated that treatment with ERT has a positive effect even in older women until the age of 75 years.

It However, there are many undesirable ones Effects associated with ERT, the patient compliance reduce. venous Thromboembolism, gallbladder disease, recurrence of menstrual bleeding, mastodynia and a possible one increased Risk of developing uterine and / or breast cancer are the risks associated with ERT. Up to 30% of the women who were prescribed ERT took the prescription not, and the deduction rate is between 38% and 70%, where Safety concerns and side effects (bloating and breakthrough bleeding) the most important reasons for the Are settling.

A new class of pharmacological agents known as Selective Estrogen Receptor Modulators or SERMs have been designed and developed as alternatives to HRT. Raloxifene, a nonsteroidal benzothiophene SERM is marketed in the US and Europe for the prevention and treatment of osteoporosis under the brand name Evista ^®. Raloxifene has been shown to reduce bone loss and prevent fracture without deleteriously stimulating uterine lining and mammary gland tissue, although raloxifene is somewhat less effective than ERT for protection against bone loss. Raloxifene is unique and significantly different from ERT in that it does not stimulate the endometrium and has the potential to prevent breast cancer. Raloxifene has also demonstrated beneficial estrogen agonist effects on cardiovascular risk factors, in particular through a rapid and sustained reduction in total and low-density lipoprotein cholesterol levels in raloxifene-treated patients. In addition, raloxifene has been shown to reduce the plasma concentration of homocysteine, an independent risk factor for atherosclerosis and thromboembolic disease.

It However, raloxifene has been reported to be associated with menopause Symptoms, such as hot flashes and vaginal dryness, worsened and cognitive function in older people Patients did not improve. Patients taking raloxifene have higher rates reported hot flashes, compared with either placebo or ERT users and about more leg cramps as a placebo user, although women who took ERT had a higher incidence vaginal bleeding and chest discomfort showed as raloxifene or Placebo users.

So far, neither Raloxifene nor any of the others currently available SERM compounds have been shown to have the ability to provide all the benefits of currently available ERT, such as controlling the menopausal syndrome and preventing AD without causing adverse side effects such as increased risk of endometrial and breast cancer and hemorrhage. Thus, there is a need for compounds that are selective estrogen receptor modulators and that provide all the benefits of ERT while also treating the vasomotor, urogenital and cognitive disorders or conditions associated with the decrease in systemic estrogen associated with the Menopause is connected.

US 3 484 435 is exemplary for the state of the art. This document discloses [2,3-d] pyrazoles of steroids of the estrane, 19-norpregnane and 19-norcholestane series. It is claimed that the compounds show estrogenic, cortical, anticholesterolaemic and pituitary blocking activity.

The Journal of Heterocyclic Chemistry (1996), 33, 539-557 also exemplary for the state of the art. This article reveals oxazole, which is incorporated into the Estrieno system is condensed into it.

SUMMARY OF THE INVENTION

worin
R¹ ausgewählt ist aus der Gruppe, bestehend aus Wasserstoff, Hydroxy, A, -O-A, C(O)-A und -SO₂-A;
n eine ganze Zahl von 0 bis 2 ist;
R² jeweils unabhängig ausgewählt ist aus der Gruppe, bestehend aus Hydroxy, Carboxy, Halogen, -A, -O-A, -C(O)-A, -C(O)O-A, Amino, (C1-C8)-Alkylamino, Di-(C1-C8)-alkylamino, Cyano, Aminocarbonyl, (C1-C8)-Alkylaminocarbonyl, Di-(C1-C8)-alkylaminocarbonyl, -SH, -S-A, -SO-A, -SO₂-A, -SO₂-NH₂, -SO₂-NH(C1-C8-Alkyl) und -SO₂-N(C1-C8-Alkyl)₂;
m eine ganze Zahl von 0 bis 2 ist;
R³ jeweils unabhängig ausgewählt ist aus der Gruppe, bestehend aus -A, -O-A, -S-A, -NH-A, -N(A)₂ und -C(O)-A;
p eine ganze Zahl von 1 bis 2 ist;
R⁴ jeweils unabhängig ausgewählt ist aus der Gruppe, bestehend Hydroxy, Carboxy, Cyano, -A, (C2-C8)-Alkenyl, -(C2-C8)-Alkinyl-A, (C2-C8)-Alkinyl, -(C2-C8)-Alkinyl-A, -O-A, -NH₂, NH(A), -N(A)₂, -N(A)-C(O)-A, -NH-C(O)-A, -C(O)-N(A)₂, -C(O)-NH₂, C(O)-NH-A, -SO₂N(A)₂, -SO₂-NH(A), -SO₂-NH₂, -N(A)-SO₂-A, -NH-SO₂-A, -C(O)O-A, -OC(O)H und -OC(O)-A;
alternativ, wenn p 2 ist, zwei R⁴-Gruppen als Oxo- oder =N(OH) zusammengenommen sein können;
q eine ganze Zahl von 0 bis 2 ist;
R⁵ jeweils unabhängig ausgewählt ist aus der Gruppe, bestehend aus Hydroxy, Carboxy, Halogen, (C1-C8)-Alkyl, (C1-C8)-Alkoxy, (C3-C8)-Cycloalkyl und -C(O)-A; wobei die (C1-C8)-Alkylgruppe fakultativ mit einem oder mehreren Substituenten substituiert ist, die unabhängig ausgewählt sind aus Halogen, Hydroxy, Carboxy oder (C1-C8)-Alkoxy; wobei A jeweils unabhängig ausgewählt ist aus der Gruppe, bestehend aus (C1-C8)-Alkyl, Aryl, Aralkyl, (C3-C8)-Cycloalkyl, Heteroaryl und Heterocycloalkyl; wobei die Aryl-, Aralkyl-, (C3-C8)-Cycloalkyl-, Heteroaryl- oder Heterocycloalkylgruppe fakultativ mit einem oder mehreren Substituenten substituiert ist, die unabhängig ausgewählt sind aus Halogen, Hydroxy, Carboxy, (C1-C4)-Alkyl, (C1-C8)-Alkoxy, Nitro, Cyano, Amino, (C1-C4)-Alkylamino oder Di-((C1-C4)-alkyl)-amino; wobei ein Heteroaryl eine fünf- oder sechsgliedrige monocyclische aromatische Ringstruktur ist, die wenigstens ein Heteroatom enthält, das ausgewählt ist aus der Gruppe, bestehend aus O, N und S, oder eine neun- oder zehngliedrige bicyclische aromatische Ringstruktur, die wenigstens ein Heteroatom enthält, das ausgewählt ist aus der Gruppe, bestehend aus O, N und S, ein Heterocycloalkyl eine fünf- bis siebengliedrige monocyclische, gesättigte oder teilweise ungesättigte Ringstruktur ist, die wenigstens ein Heteroatom enthält, das ausgewählt ist aus der Gruppe, bestehend aus O, N und S, oder ein neun- bis zehngliedriges gesättigtes, teilweise ungesättigtes oder teilweise aromatisches bicyclisches Ringsystem, das wenigstens ein Heteroatom enthält, das ausgewählt ist aus der Gruppe, bestehend aus O, N und S, und ein Aryl eine carbocyclische aromatische Gruppe ist;
oder ein pharmazeutisch annehmbares Salz davon.The present invention is directed to a compound of formula (I) or (II)

wherein
R ^{1 is} selected from the group consisting of hydrogen, hydroxy, A, -OA, C (O) -A and -SO ₂ -A;
n is an integer from 0 to 2;
Each R ² is independently selected from the group consisting of hydroxy, carboxy, halo, -A, -OA, -C (O) -A, -C (O) OA, amino, (C 1 -C 8) alkylamino, di - (C 1 -C 8) -alkylamino, cyano, aminocarbonyl, (C 1 -C 8) -alkylaminocarbonyl, di- (C 1 -C 8) -alkylaminocarbonyl, -SH, -SA, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (C 1 -C 8 -alkyl) and -SO ₂ -N (C 1 -C 8 -alkyl) ₂ ;
m is an integer of 0 to 2;
Each R ³ is independently selected from the group consisting of -A, -OA, -SA, -NH-A, -N (A) ₂ and -C (O) -A;
p is an integer of 1 to 2;
Each R ⁴ is independently selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, - (C 2 -C 8) -alkynyl-A, (C 2 -C 8) -alkynyl, - (C 2 -C8) alkynyl-A, -OA, -NH ₂ , NH (A), -N (A) ₂ , -N (A) -C (O) -A, -NH-C (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , C (O) -NH-A, -SO ₂ N (A) ₂ , -SO ₂ -NH (A), -SO ₂ -NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O) -A;
alternatively, when p is 2, two R ⁴ groups may be taken together as oxo or = N (OH);
q is an integer from 0 to 2;
Each R ⁵ is independently selected from the group consisting of hydroxy, carboxy, halo, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 3 -C 8) cycloalkyl, and -C (O) -A; wherein the (C 1 -C 8) alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy or (C 1 -C 8) alkoxy; each A is independently selected from the group consisting of (C 1 -C 8) alkyl, aryl, aralkyl, (C 3 -C 8) cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, (C3-C8) -cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, (C1-C4) -alkyl, ( C 1 -C 8) -alkoxy, nitro, cyano, amino, (C 1 -C 4) -alkylamino or di- ((C 1 -C 4) -alkyl) -amino; wherein a heteroaryl is a five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom, which is selected from the group consisting of O, N and S, a heterocycloalkyl is a five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- to ten-membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, and an aryl is a carbocyclic aromatic group;
or a pharmaceutically acceptable salt thereof.

Illustrative for the Invention is a pharmaceutical composition comprising a pharmaceutical acceptable carrier and one of the compounds described above. An illustration The invention is a pharmaceutical composition prepared is by mixing one of the compounds described above and a pharmaceutically acceptable carrier. Illustrating the invention is a process for the preparation of a pharmaceutical composition, which is the mixing of one of the compounds described above and a pharmaceutically acceptable carrier.

The Exemplifying the invention is the use of those described above Compounds or pharmaceutical compositions in the preparation of a drug used to treat a disorder caused by or several estrogen receptors is mediated.

One another example of The invention is the use of any of those described herein Compounds in the manufacture of a medicament for treatment of: (a) hot flashes, (b) vaginal dryness, (c) osteopenia, (d) osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function, (g) degenerative brain disease, (h) a cardiovascular Disease, (i) a cerebrovascular disease, (j) breast cancer, (k) uterine cancer, (c) cervical cancer, (m) prostate cancer, (n) benign prostatic hyperplasia, (o) endometriosis, (p) uterine fibroids, (q) osteoarthritis and for (r) contraception a person who needs it.

DETAILED DESCRIPTION OF THE INVENTION

worin R¹, n, R², m, R³, p, R⁴, q und R⁵ sind wie hierin definiert sind. Die Verbindungen der vorliegenden Erfindung sind Modulatoren eines Estrogen-Rezeptors, die nützlich sind für die Behandlung und Verhinderung von Störungen, die mit Estrogenmangel verbunden sind, einschließlich, aber nicht beschränkt auf Hitzewallungen, vaginale Trockenheit, Osteopenie, Osteoporose, Hyperlipidämie, Verlust kognitiver Funktion, degenerative Hirnerkrankung, kardiovaskuläre Erkrankungen und zerebrovaskuläre Erkrankungen; für die Behandlung von hormonempfindlichen Krebserkrankungen und Hyperplasie (in Geweben, die Brust, Gebärmutterschleimhaut und Gebärmutterhals bei Frauen und Prostata bei Männern einschließen); für die Behandlung und Verhinderung von Endometriose, Gebärmutterfibroiden und Osteoarthritis; und als Empfängnisverhütungsmittel, entweder allein oder in Kombination mit einem Progestogen oder Progestogen-Antagonisten.The present invention is directed to compounds of formula (I) or (II)

wherein R ¹ , n, R ² , m, R ³ , p, R ⁴ , q and R ⁵ are as defined herein. The compounds of the present invention are estrogen receptor modulators useful for the treatment and prevention of estrogen-deficient disorders including, but not limited to, hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, cardiovascular diseases and cerebrovascular diseases; for the treatment of hormone-sensitive cancers and hyperplasia (in tissues that include the breast, uterine lining and cervix in women and the prostate in males); for the treatment and prevention of endometriosis, uterine fibroids and osteoarthritis; and as a contraceptive, either alone or in combination with a progestogen or progestogen antagonist.

In an embodiment The present invention is a compound of formula (I) .In another embodiment The present invention is a compound of formula (II).

In a further embodiment of the present invention, R ^{1 is} selected from the group consisting of hydrogen, hydroxy, (C 1 -C 8) -alkyl, aryl, aralkyl, -O- (C 1 -C 8) -alkyl, -O-aryl, O-aralkyl, C (O) -A and -SO ₂ -A. In another embodiment of the present invention, R ^{1 is} selected from the group consisting of hydrogen and -SO ₂ -A. Preferably, R ^{1 is} selected from the group consisting of hydrogen and -SO- (C ¹ -C 8) alkyl, more preferably R ^{1 is} hydrogen or methylsulfonyl.

In an embodiment In the present invention, A is selected from the group consisting from (C 1 -C 8) -alkyl, aryl and aralkyl; where the (C 1 -C 8) -alkyl, aryl or aralkyl group is optionally substituted with one or more, preferably one to three, more preferably one to two substituents, the independent selected are halogen, hydroxy, carboxy, (C 1 -C 4 -alkyl, (C 1 -C 4) -alkoxy, Nitro, cyano, amino, (C 1 -C 4) -alkylamino or di (C 1 -C 4) alkyl) amino.

In one embodiment of the present invention, n is an integer from 0 to 1, preferably n is 0. In one embodiment of the present invention, R ^{2 is} selected from the group consisting of carboxy, halo, -A, -C (O) - A, -C (O) OA, cyano, -SA, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (alkyl) and -SO ₂ -N (alkyl) ₂ , Preferably, R ^{2 is} selected from the group consisting of -SA, more preferably R ^{2 is} selected from the group consisting of -S - ((C 1 -C 8) alkyl), more preferably R ^{2 is} methylthio.

In an embodiment In the present invention, m is an integer of 0 to 1, preferably m 0.

In one embodiment of the present invention, R ^{2 is} selected from the group consisting of -A, -OA, -SA, -NH-A, and -C (O) -A.

In one embodiment of the present invention p is from 1 to 1. In one embodiment of the present invention, R ^{4 is} selected from the group consisting of hydroxy and -OC (O) -A. Preferably, R ^{4 is} selected from the group consisting of hydroxy, -OC (O) - (C 1 -C 8 -alkyl), -OC (O) - (C 1 -C 8 -alkyl) -CO ₂ H, and alkynyl. More preferably, R ^{4 is} selected from the group consisting of hydroxy, n-butylcarbonyloxy, n-carboxy-n-butylcarbonyloxy, and ethynyl.

In one embodiment of the present invention p is 2 and two R ⁴ groups are taken together as oxo or = N (OH). Preferably p is 2 and two R ⁴ groups taken together are oxo.

In one embodiment of the present invention, R ^{4 is} selected from the group consisting of hydroxy, -NH ₂ , -NH (A), -C (O) NH ₂ , -C (O) -NH (A), -SO ₂ -NH ₂ , -SO ₂ NH (A) and -OC (O) -A, and is the R ⁴ group in a β orientation. In a further embodiment of the present invention, R ^{4 is} selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, (C 2 -C 8) -alkenyl-A, (C 2 -C 8) - Alkynyl, - (C ₂ -C 8) alkynyl-A, -OA, -NH ₂ , -NH (A), -N (A) ₂ , N (A) -C (O) -A, -NH-C- (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , -C (O) -NH-A, -SO ₂ -N (A) ₂ , -SO ₂ -NH (A), -SO ₂ -NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O ) -A, and is the R ⁴ group in an α orientation. In another embodiment of the present invention, R ^{4 is} selected from the group consisting of hydroxy, carboxy, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkenyl, and C ₁ -C ₄ alkynyl, and is in an alpha orientation. In yet another embodiment of the present invention, two R ⁴ groups are taken together as oxo or = N (OH).

In an embodiment In the present invention, q is an integer of 0 to 1, preferably q 0.

In one embodiment of the present invention, R ^{5 is} selected from the group consisting of carboxy, halo, C 1 -C 4 alkyl and -C (O) -A. Preferably, R ^{5 is} hydrogen.

Tabelle 2

Representative compounds of the formula (I) and (II) of the present invention are listed in Tables 1 and 2. Table 1

Table 2

As used herein, the term "halogen" shall, unless otherwise indicated, chlorine, Bromine, fluorine and iodine mean.

As used herein the term "alkyl" unless otherwise stated indicated either alone or as part of a substituent group, straight and branched carbon chains. Alkyl groups include Example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Preferably, the alkyl group contains one to eight carbon atoms. Unless otherwise indicated, "lower" when alkyl uses a carbon chain composition having one to four Carbon atoms.

As As used herein, the term "alkenyl" shall be used unless otherwise stated used alone or as part of a substituent group, even and include branched chains, the at least one unsaturated Double bond included. For example, vinyl, propenyl or allyl, Butenyl, buten-2-yl, buten-3-yl, 2-methylbutene-2-yl and the like. Preferably contains the alkenyl group has two to eight carbon atoms. Unless otherwise indicates "lower" when alkenyl used a carbon chain composition with two to eight Carbon atoms containing at least one unsaturated double bond.

As used herein, the term "alkynyl", unless otherwise indicated, whether used alone or as part of a substituent group, even and include branched chains, the at least one unsaturated Triple bond included. For example, ethynyl, propynyl, butyn-2-yl and the same. Preferably, the alkynyl group contains two to eight carbon atoms. Unless otherwise indicated, "lower" when alkynyl uses a carbon chain composition having two to four Carbon atoms containing at least one unsaturated triple bond.

As used herein is intended to mean "alkoxy" unless otherwise specified indicated an oxygen ether radical of the above described straight or branched-chain alkyl groups. For example, methoxy, Ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.

As used herein is intended to be "aryl" unless otherwise stated refer to a carbocyclic aromatic group, such as such as phenyl, naphthyl and the like.

As used herein is intended to mean "aralkyl" unless otherwise specified , a lower alkyl group represented by an aryl group substituted, such as phenyl, naphthyl and the like. To the For example, benzyl, phenylethyl, phenylpropyl, naphthylmethyl and the like.

As As used herein, the term "cycloalkyl" is intended, unless otherwise specified given a stable three to eight, preferably five to eight, more preferably five mean up to six-membered monocyclic, saturated ring system, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein is intended to mean "heteroaryl" unless otherwise stated indicated, a five- or six-membered monocyclic aromatic ring structure, which contains at least one heteroatom selected from the group consisting of O, N and S, optionally one to three additional Heteroatoms containing independently selected from the group consisting from O, N and S; or a nine- or ten-membered bicyclic aromatic Ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally one to four additional Heteroatoms containing independently selected from the group consisting from O, N and S. The heteroaryl group can be attached to any heteroatom or Carbon atom of the ring be bound so that the result is a stable structure is.

Examples for suitable Close heteroaryl groups Pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, Isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, Pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, Indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, Quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, Phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl and the like, but are not limited thereto.

As As used herein, the term "heterocycloalkyl" is intended to be a five- to four-membered alkyl group seven-membered monocyclic, saturated or partially unsaturated ring structure which contains at least one heteroatom selected from the group consisting of O, N and S, optionally one to three additional Heteroatoms containing independently selected from the group consisting from O, N and S; or a nine- to ten-membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least contains a heteroatom, that selected is from the group consisting of O, N and S, optionally one to four additional ones Heteroatoms containing independently selected from the group consisting from O, N and S. The heterocycloalkyl group can be attached to any heteroatom or carbon atom of the ring so be bound that the result a stable structure is.

Examples for suitable Close heteroaryl groups Pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, Pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, Dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, Chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl and the like, but are not limited.

As As used herein, the term "*" is intended to indicate the presence of a stereogenic Center designate.

If a particular group "substituted" is, for example, aryl, Aralkyl, cycloalkyl, heterocycloalkyl, heteroaryl), may be that group have one or more substituents, preferably of one to five Substituents, more preferably from one to three substituents, still more preferably one to two substituents independently selected from the list of substituents.

Under Referring to substituents, the term "independent" means that if more as one of such substituents is possible, such substituents may be identical or different from each other.

Under standard nomenclature used throughout this disclosure, the end portion of the designated side chain is described first, followed by the adjacent functionality towards the point of attachment. For example, a "phenylalkylaminocarbonylalkyl" substituent refers to a group of the formula

Provided not stated otherwise, the position of substituents is intended to be the core structures of the compounds of formula (I) and (II) the base of the following numbering system.

The position of substituent (s) on a compound of formula (I) shall be numbered to number the nucleus of rings A, B, C and D based on accepted convention, and the fifth E-ring positions with the lower case letters a , b and c, beginning at the N atom, are as follows:

The position of substituent (s) on a compound of formula (II) shall be referred to similarly as follows:

For the compounds of the present invention, each R ⁴ substituent may be in an α- or a β-orientation, wherein in the α-orientation the R ⁴ group is below the plane of the core molecule and in the β-orientation the R ⁴ Group is above the level of the core molecule.

Ac

= Acetyl

AcOH

= Essigsäure

BlNAP

= 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl

BnOH

= Benzylalkohol

Bu₃N

= Tributylamin

DCC

= N,N'-Dicyclohexylcarbodiimid

DCM

= Dichlormethan

DIC

= N,N'-Diisopropylcarbodiimid

DIPEA

= Diisopropylethylamin

DMAP

= 4-N,N-Dimethylaminopyridin

DMF

= N,N-Dimethylformamid

DMSO

= Dimethylsulfoxid

DPPE

= 1,2-Bis(diphenylphosphino)-ethan

DPPP

= 1,3-Bis(diphenylphosphino)-propan

Et₂O

= Diethylether

EtOAc

= Ethylacetat

EtOH

= Ethanol

HEPES

= 4-(2-Hydroxyethyl)-1-piperazinethansulfonsäure

LDA

= Lithiumdiisopropylamin

LHMDS

oder LiHMDS = Lithiumbis(trimethylsilyl)amid

mCPBA

= meta-Chlorperoxybenzoesäure

Me

= Methyl (d. h. -CH₃)

MeOH

= Methanol

NaO-t-Bu

= Natrium-t-butoxid

NBS

= N-Bromsuccinimid

NIS

= N-Iodsuccinimid

NMO

= N-Methylmorpholinoxid

PBS

= phosphatgepufferte Salzlösung

Pd(OAc)₂

= Palladium(II)-acetat

Pd₂(dba)₃

= Tris(dibenzylidenaceton)dipalladium(0)

Pd(PPh₃)₂Cl₂

= Dichlorbis(triphenylphosphin)palladium(II)

Ph

= Phenyl

PhSO₂

= Phenylsulfonyl

PhSO₂Cl

= Phenylsulfonylchlorid

PPA

= Polyphosphorsäure

PPh₃ oder Ph₃P

= Triphenylphosphin

PISA

= p-Toluolsulfonsäure

t-Bu

= t-Butyl

t-BuoCl

= t-Butoxychlorid

t-BuOH

= t-Butanol

t-BuOK

= Kalium-t-butoxid

t-BuONa

= Natrium-t-butoxid

TEA oder Et₃N

= Triethylamin

TFA

= Trifluoressigsäure

THF

= Tetrahydrofuran

Abbreviations used in the description, in particular the schemes and examples, are as follows:

Ac

= Acetyl

AcOH

= Acetic acid

BlNAP

= 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl

BnOH

= Benzyl alcohol

Bu ₃ N

= Tributylamine

DCC

= N, N'-dicyclohexylcarbodiimide

DCM

= Dichloromethane

DIC

= N, N'-diisopropylcarbodiimide

DIPEA

= Diisopropylethylamine

DMAP

= 4-N, N-dimethylaminopyridine

DMF

= N, N-dimethylformamide

DMSO

= Dimethyl sulfoxide

DPPE

= 1,2-bis (diphenylphosphino) ethane

DPPP

= 1,3-bis (diphenylphosphino) -propane

Et ₂ O

= Diethyl ether

EtOAc

= Ethyl acetate

EtOH

= Ethanol

HEPES

= 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid

LDA

= Lithium diisopropylamine

LHMDS

or LiHMDS = lithium bis (trimethylsilyl) amide

mCPBA

= meta-chloroperoxybenzoic acid

me

= Methyl (ie -CH ₃ )

MeOH

= Methanol

NaO-t-Bu

= Sodium t-butoxide

NBS

= N-bromosuccinimide

NIS

= N-iodosuccinimide

NMO

= N-methylmorpholine oxide

PBS

= phosphate buffered saline solution

Pd (OAc) ₂

= Palladium (II) acetate

Pd ₂ (dba) ₃

= Tris (dibenzylideneacetone) dipalladium (0)

Pd (PPh ₃ ) ₂ Cl ₂

= Dichlorobis (triphenylphosphine) palladium (II)

Ph

= Phenyl

PhSO ₂

= Phenylsulfonyl

PhSO ₂ Cl

= Phenylsulfonyl chloride

PPA

= Polyphosphoric acid

PPh ₃ or Ph ₃ P

= Triphenylphosphine

PISA

= p-toluenesulfonic acid

t-Bu

= t-butyl

t-BuoCl

= t-butoxy chloride

t-BuOH

= t-butanol

t-BuOK

= Potassium t-butoxide

t-BuONa

= Sodium t-butoxide

TEA or Et ₃ N

= Triethylamine

TFA

= Trifluoroacetic acid

THF

= Tetrahydrofuran

As As used herein, the term "disease or disorder that is is modulated or mediated by an estrogen receptor, each Illness or disorder mean, which mediates through the estrogen α receptor will, any disease or disorder, by the estrogen-β receptor or any disease or disorder caused by both the Estrogen α- as well as the estrogen β receptor is taught. For example, hot flashes, vaginal dryness, Osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain disease, cardiovascular disease, cerebrovascular disease, breast cancer, Uterine cancer, cervix, Prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, Osteoarthritis and contraception.

As used herein, is the term "degenerative brain disease" cognitive disorder, dementia (regardless of the underlying cause) and Alzheimer's disease lock in.

As As used herein, the term "cardiovascular disease" is intended to include elevated blood lipid levels, coronary arteriosclerosis and coronary heart disease.

As Used herein, the term "cerebrovascular disease" is intended to be abnormal regional cerebral bloodstream and ischemic brain injury lock in.

As used herein is the term "progestogen antagonist" mifepristone (RU-486), J-867 (Jenapharm / TAP Pharmaceuticals), J-956 (Jenapharm / TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638 (Organon), ORG-31806 (Organon), Onapristone (ZK98299) and Include PRA248 (Wyeth).

Of the Term "person" as used herein refers to an animal, preferably a mammal, most preferably one People who are the subject of treatment, observation or Experiment is.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent which has the biological or medicinal response in a Ge tissue system, animal, or human being desired by a researcher, veterinarian, medical doctor, or other clinician, including alleviating the symptoms of the disorder or disorder to be treated. Where the present invention is directed to co-therapy involving the administration of one or more compounds of formula (I) or (II) and a progestogen or progestogen antagonist, "therapeutically effective amount" shall mean that amount of the combination of agents. For example, the therapeutically effective amount of co-therapy comprising the administration of a compound of formula (I) and progestogen would be the amount of the compound of formula (I) which is taken together such that the combined effect produces the desired biological or medical response. I) and the amount of progestogen which, when taken together or sequentially, have a combined effect that is therapeutically effective Further, it will be appreciated by one skilled in the art that in the case of co-therapy with a therapeutically effective amount as described in U.S. Pat above example, the amount of the compound of formula (I) and / or the amount of progestogen or progestogen Antagonists may be therapeutically effective individually or not.

As used herein, the term "co-therapy" is intended to mean the treatment of a Person in need of it, by administering one or more Compounds of formula (I) or (II) with a progestogen or Progestogen antagonists mean that the compound (s) of Formula (I) or (II) and the progestogen or the progestogen antagonist with all be administered by appropriate means, simultaneously, consecutively, separately or in a single pharmaceutical formulation. Where the compound (s) of formula (I) or (II) and the progestogen or the progestogen antagonist can be administered in separate dosage forms, the number of dosages per day for each compound administered is identical or different. The compound (s) of formula (I) or (II) and the progestogen or the progestogen antagonist can about the same or different routes of administration are administered. Examples for suitable Close administration methods oral, intravenous (iv), intramuscularly (im), subcutaneous (sc), transdermal and rectal, but are not limited to this. Connections can also be administered directly to the nervous system, including, but not limited on, intracerebral, intraventricular, intracerebroventricular, intrathecal, intracistemal, intraspinal and / or perispinal routes of administration, by delivery via intracranial or intravertebral needles and / or catheters, with or without pumping devices. The compound (s) of formula (I) or (II) and the progestogen or the progestogen antagonist may be according to simultaneous or alternating Regimes are administered to the same or different Times during the course of therapy, simultaneously in subdivided or individual To shape.

As As used herein, the term "composition" is intended to include a product, the specified ingredients in the specified amounts comprises as well as any product that, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." However, other salts may be useful in preparing compounds of this invention or their pharmaceutically acceptable salts Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric, sulfuric, fumaric, maleic, succinic, acetic, benzoic, citric, tartaric, carbonic or phosphoric acid Compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof, alkali metal salts, for example sodium or potassium salts, alkaline earth metal salts, for example calcium or magnesium salts, and salts containing suitable organic ligands be formed, for example, quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarananilate, hexylresorcinate, Hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate) , Palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Schema 1 Compounds of formula (I) and (II) wherein R ^{4 is} oxo may be prepared according to the procedure outlined in Scheme 1.

Scheme 1

Accordingly, an appropriately substituted compound of formula (III), a known compound or compound prepared by known methods, is reacted with 1,1,2,2,3,3,3-heptafluoropropane-1-sulfonyl fluoride (ie, CF ₃ (CF ₂ ) ₃ SO ₂ F), a known compound, in the presence of a base such as TEA, DIPEA, pyridine and the like, in an organic solvent such as DCM, THF, DMF and the like, to obtain the corresponding compound of formula (IV ) to deliver.

The compound of formula (IV) is reacted with 2,2-diethoxyethylamine, a known compound, in the presence of a phosphine ligand, such as BTNAP, DPPP, DPPE and the like, in the presence of a Ka catalysts, such as Pd (OAc) ₂ , Pd ₂ (dba) ₃ , Pd (PPh ₃ ) ₂ Cl ₂ and the like, in the presence of a base such as sodium t-butoxide, Cs ₂ CO ₃ , K ₂ CO ₃ and the like, reacted to provide the corresponding compound of formula (V).

The compound of formula (V) is reacted with a suitable protecting agent such as CH ₃ SO ₂ Cl, PhSO ₂ Cl, CH ₃ COCl, (CF ₃ CO) ₂ O and the like in the presence of a base such as TEA, DIPEA, Pyridine and the like, in an organic solvent such as DCM, THF, DMF and the like, to provide the corresponding compound of formula (VI) wherein PG ^{1 is} a protecting group such as CH ₃ SO ₂ , PhSO ₂ , Ac , CF ₃ CO and the like.

The Compound of formula (VI) is reacted with an acid such as PPA, PISA, sulfuric acid and the like, in an organic solvent such as toluene, Xylene and the like, reacted to a mixture of the compounds of formula (VII) and (VIII).

From The compounds of formula (VII) and (VIII) are the protecting groups according to known Methods cleaved to the corresponding compounds of formula (Ia) and (IIa).

Preferably the compounds of formula (Ia) and (IIa) with known Methods separated. Alternatively, the compounds of formula (VII) and (VIII) separated by known methods and from these then individually deprotected with known methods, to the corresponding compounds of formula (Ia) and (IIa) deliver.

A person skilled in the art will recognize that compounds of formula (I) and / or (II) in which p is 2 and two R ⁴ groups are taken together as = N (OH), from the corresponding compound of formula (I) and / or (II) can be prepared in which p is 2 and two R ⁴ groups are taken together as oxo, by the compound of formula (I) and / or (II) in which p is 2 and two R ⁴ groups as oxo, is reacted with hydroxylamine in an organic solvent such as ethanol, methanol, isopropanol and the like.

Schema 2 Compounds of formula (I) and / or (II) in which R ^{4 is} hydroxy may be prepared from the corresponding compound of formula (I) or (II) in which R ^{4 is} oxo. As an example, Scheme 2 describes a process for the preparation of compounds of formula (I) in which R ^{4 is} other than oxo.

Scheme 2

More specifically, a suitably substituted compound of formula (VII) prepared as in Scheme 1 above with a reducing agent such as NaBH ₄ , LiBH ₄ , LiAlH ₄ and the like in a polar organic solvent such as methanol, ethanol, isopropanol and the like the like, to provide the corresponding compound of formula (IX).

From the compound of formula (IX), the protecting group is cleaved by known methods to to provide the corresponding compound of formula (Ic).

One skilled in the art will recognize that compounds of formula (II) in which R ^{4 is} hydroxy can be prepared in a similar manner according to the procedure outlined in Scheme 1 by reacting the compound of formula (VII) with the compound of formula (VIII) is replaced.

Schema 3 Compounds of formula (I) wherein p is 2 and R ⁴ is other than oxo or = N (OH) can be prepared according to the procedures outlined in Scheme 3.

Scheme 3

Accordingly, a compound of formula (VII) prepared as in Scheme 1 above with an appropriately substituted compound of formula (X) in the presence of a lithium organic agent such as alkyllithium, aryllithium, alkenyllithium, alkynyllithium and the like, in an organic Solvents such as THF, diethyl ether and the like are reacted to provide the corresponding compound of formula (XII). The use of a compound of formula (X) is particularly preferred for introducing R ⁴ groups selected from -A, alkenyl, alkynyl, alkenyl-A and alkynyl-A.

Alternatively, a compound of formula (VII) prepared as in Scheme 1 above with a suitably substituted compound of formula (XI) wherein X is Cl, Br or I, a Grignard reagent such as alkylmagnesium halide, arylmagnesium halide, alkenylmagnesium halide, Alkynylmagnesium halide and the like, in an organic solvent such as THF, diethyl ether, dioxolane and the like, to provide the corresponding compound of formula (XII). The use of a compound of formula (XI) is especially preferred for the introduction of R ⁴ groups selected from -A, alkenyl, alkynyl, alkenyl-A and alkynyl-A.

From the compound of formula (XII) is deprotected according to known methods cleaved to the corresponding compound of formula (Id) deliver.

One One skilled in the art will recognize that the compounds of formula (II) are more similar Way according to the in Scheme 3 outlined by the compound of formula (VII) by the compound of formula (VIII) is replaced.

Schema 4 Compounds of formula (I) in which p is 1 and R ^{4 is} selected from -O-alkyl, -O-aralkyl, -O-cycloalkyl, -O-heterocycloalkyl or -OC (O) -A, may be prepared according to the procedure described in Scheme 4 outlined procedures.

Scheme 4

Accordingly, a compound of formula (IX) prepared as in Scheme 2 above with a suitably substituted compound of formula (XIV) wherein W is a leaving group such as Cl, Br, I, tosylate, mesylate, triflate and the like, and wherein R ^{4a is} selected from the group consisting of alkyl, aralkyl, cycloalkyl and heterocycloalkyl, in the presence of a base such as pyridine, TEA, imidazole and the like, in an organic solvent such as DCM, THF, DMF and the like, optionally in the presence of a catalyst, such as DMAP and the like, to provide the corresponding compound of formula (XVI), wherein R ^{4 is} selected from -O-alkyl, -O-aralkyl, -O-cycloalkyl or -O-heterocycloalkyl ,

Alternatively, a compound of formula (IX) prepared as in Scheme 2 above with a suitably substituted anhydride (a compound of the formula R ^4a -C (O) OC (O) -R ^4a ) wherein R ^{4a is} selected from the group consisting of: A group consisting of alkyl, aralkyl, cycloalkyl, heterocycloalkyl and -C (O) -A, in the presence of a base such as pyridine, TEA, imidazole and the like, in an organic solvent such as DCM, THF, diethyl ether and the like, optionally in the presence of a catalyst DMAP and the like, to provide the corresponding compound of formula (XVI) wherein R ^{4 is} selected from -OC (O) -A.

Alternatively, a compound of formula (IX) prepared as in Scheme 2 above with a suitably substituted compound of formula (XV) wherein Q is OH, Cl or Br and wherein R ^{4b is} selected from the group consisting of alkyl, Aralkyl, cycloalkyl and heterocycloalkyl, to provide the corresponding compound of formula (XVI). Where in the compound of (XV) Q is Cl or Br, the compound of formula (IX) is reacted with the compound of formula (XV) in the presence of a base such as pyridine, TEA, imidazole and the like in an organic solvent such as such as DCM, THF, diethyl ether and the like, optionally in the presence of a catalyst DMAP and the like, to provide the corresponding compound of formula (XVI). Where in the compound of formula (XV) Q is OH, the compound of formula (IX) is reacted with the compound of formula (XV) in the presence of a coupling agent such as DCC, DIC and the like in an organic solvent such as THF , Diethyl ether, DCM, acetonitrile and the like, to provide the corresponding compound of formula (XVI) wherein R ^{4 is} selected from -OC (O) -A.

From the compound of formula (XVI) is deprotected according to known methods cleaved to give the corresponding compound of formula (Ie) deliver.

A person skilled in the art will recognize that a compound of formula (II) wherein p is 1 and R ^{4 is} selected from -O-alkyl, -O-aralkyl, -O-cycloalkyl, -O-heterocycloalkyl or -OC (O) - A, can be prepared in a similar manner according to the procedure outlined in Scheme 4, with replacement of the compound of formula (IX) with a compound of formula (XIII).

Schema 5 Compounds of formulas (I) and (II) wherein n is 1 and the R ² group is attached to the carbon atom adjacent to the N atom of the E ring can be prepared according to the procedure outlined in Scheme 5.

Scheme 5

Accordingly, an appropriately substituted compound of formula (XVII), a known compound or compound prepared by known methods, with an iodinating agent such as NIS, iodine, ICl and the like, in the presence of a coupling agent such as PISA and the like, or a Lewis Acid, such as zinc chloride, BF ₃ · etherate and the like, in an organic solvent, such as methanol, ethanol, THF, DMSO, DMF and the like, to give a mixture of the corresponding compounds of formula (XVIII) and (XIX) to deliver.

Optional the compounds of formula (XVIII) and (XIX) are known with Methods separated.

The mixture of compounds of formula (XVIII) and (XIX) is reacted with a suitably substituted compound of formula (XX), a known compound or a compound prepared by known methods, in the presence of a coupling agent such as Pd (PPh ₃ ) ₂ Cl ₂ , Pd (dba) ₂ and the like, optionally in the presence of CuI, in an organic solvent such as TEA, DIPEA, pyridine and the like, optionally in an organic solvent such as methylene chloride, DCM, THF, benzene and the like, reacted to provide a mixture of the corresponding compounds of formula (XXI) and (XXII).

Optional the compounds of formula (XXI) and (XXII) with known Methods separated.

The Mixture of the compounds of formula (XXI) and (XXII) is with CuI in an organic solvent, such as benzene, toluene, DMF and the like, at an elevated temperature in the range of about 50 to about 110 ° C reacted to the corresponding To provide compounds of formula (If) and (IIf).

Preferably the compounds of formula (If) and (IIf) with known Methods separated.

Schema 6 Compounds of formulas (I) and (II) wherein n is 1 and the R ² group is attached to the carbon atom adjacent to the N atom of the E ring may alternatively be prepared according to the procedure outlined in Scheme 6.

Scheme 6

Accordingly, a suitably substituted compound of formula (Ib) or suitable substituted compounds of formula (IIb) or mixture thereof (as exemplified herein), a known compound or Compound prepared as described in the above schemes, with a suitably substituted compound of formula (XXIII), wherein W is a leaving group, such as Cl, Br, I, tosylate, mesylate, triflate and the like, a known compound or known methods prepared in the presence of a base such as LDA, LHMDS, t-butyllithium and the like, in an organic solvent, such as THF, diethyl ether, dioxolane and the like, reacted, to the mixture of the corresponding compounds of formula (Ic) and (IIc).

Preferably the N atom on the E-ring of the compound of formula (Ib) and (IIb) before reacting with the compound of formula (XXIII) with protected by known methods and subsequently the protective group cleaved by known methods.

Preferably the compounds of formula (Ic) and (IIc) with known Methods separated.

Schema 7 Compounds of formulas (I) and (II) in which n is 1 and the R ² group is a carbon atom away from N (ie at the beta position) or where n is 2 may be prepared according to the procedure outlined in Scheme 7 Process are produced.

Scheme 7

Accordingly, an appropriately substituted compound of formula (Ig) or compound of formula (IIg) or mixture thereof (as exemplified in the scheme herein) with an appropriately substituted compound of formula (XXIII) wherein W is a leaving group, such as Cl, Br, I, tosylate, mesylate, triflate and the like, a known compound or a compound prepared by known methods, in the presence of a catalyst such as AlCl ₃ , ZnCl ₂ and the like in an organic solvent such as methylene chloride, DCM, benzene and the like the like reacted to provide a mixture of the corresponding compounds of formula (Ih) and (IIh).

Preferably the compounds of formula (Ih) and (IIh) with known Methods separated.

Schema 8 Compounds of formula (II) in which n is 1, R ^{2 is} selected from -SA and the R ² group is attached to the carbon adjacent to the N atom (ie at the alpha position) may be prepared according to the procedure outlined in Scheme 8 outlined methods are produced.

Scheme 8

Accordingly, a Compound of formula (XXIV), a known compound or with prepared with known methods, with t-butoxychloride and a compound of formula (XXV), a known compound or compound prepared by known methods, in the presence a base such as TEA, DIPEA, pyridine and the like, in one organic solvents, such as DCM, chloroform and the like, reacted to give the corresponding To provide compound of formula (IIj).

Schema 9 Compounds of formula (I) wherein R ^{1 is} selected from -OH or -OA can be prepared according to the procedure outlined in Scheme 9.

Scheme 9

Accordingly, an appropriately substituted compound of formula (Ik) is reacted with a reducing agent such as H ₂ , 1,4-cyclohexadiene, triethylsilane, sodium cyanoborohydride, borane and the like in the presence an acid such as HCl, TFA, BF ₃ · etherate and the like, in an organic solvent such as methanol, ethanol, THF and the like, to provide the corresponding compound of formula (XXVI).

The compound of formula (XXVI) is reacted with an oxidizing agent such as H ₂ O ₂ , NMO and the like in the presence of a catalyst such as NaH ₂ PO ₂ , Na ₂ WO ₄ , NaIO ₄ and the like in an organic solvent. such as methanol, pyridine, AcOH and the like, reacted to provide the corresponding compound of formula (Im), a compound of formula (I) wherein the R ¹ group is -OH.

The compound of formula (Im) is optionally (to displace the H atom on the OH group) with an appropriately substituted reagent such as A-halo, A-tosylate, A-mesylate, A-triflate, AC (O ) -Halogen, A-SO ₂ -halogen, a symmetrical anhydride (eg AC (O) OC (O) -A), an asymmetric anhydride (eg AC (O) OC (O) -A ' ), a cyclic anhydride and the like, in the presence of a base such as NaH, t-BuOK, NaOH and the like in an organic solvent such as THF, DCM, dioxolane, DMSO, DMF and the like to the corresponding compound of formula (In) reacted, a compound of formula (I) wherein the R ¹ group is OA, -C (O) -A or -SO ₂ -A.

Schema 10 Compounds of formula (I) wherein R ^{1 is} selected from -A, -C (O) -A or -SO ₂ -A can be prepared according to the procedure outlined in Scheme 10.

Scheme 10

Accordingly, a suitably substituted compound of formula (Ik) is reacted with an appropriately substituted reagent such as AC (O) -halogen, A-SO ₂ -halogen, an asymmetric anhydride (e.g., AC (O) OC (O) - A '), a symmetrical anhydride (e.g., AC (O) OC (O) -A), a cyclic anhydride, and the like, in the presence of a base such as NaH, t-BuOK, NaOH, and the like, in an organic Solvents such as THF, DCM, dioxolane, DMSO, DMF and the like are reacted to provide the corresponding compound of formula (Ip) wherein the R ¹ group is selected from -A (wherein A is other than aryl or heteroaryl ), -C (O) -A or -SO ₂ -A.

For compounds of formula (I) wherein R ^{1 is} -A and A is vinyl, aryl or heteroaryl, the compound of formula (Ik) is reacted with an appropriately substituted reagent such as vinyl halide, (aryl or heteroaryl) halide, (Aryl or heteroaryl) triflate, in the presence of a catalyst such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd ₂ (dba) ₃ , CuI, CuBr and the like, in the presence of a base such as Cs ₂ CO ₃ , t-BuONa, CsF, K ₂ CO ₃ and the like, in the presence of a ligand such as DPPP, DPPE, Ph ₃ P, BINAP and the like, in an organic solvent such as toluene, dioxolane, DMF and the like and the like, to provide the corresponding compound of formula (Ip) wherein R ^{1 is} A and A is vinyl, aryl or heteroaryl.

One skilled in the art will recognize that compounds of formula (II) wherein R ^{1 is} selected from -OH, -OA, -A, -C (O) -A, or -SO ₂ -A, similarly as described in Scheme 9 and 10 can be prepared, with replacement of the compound of formula (Ik) by an appropriately substituted compound of formula (IIk)

One skilled in the art will further recognize that the compound of formula (Ik) in Schemes 9 and 10 above can be replaced by a mixture of a compound of formula (Ik) and a compound of formula (IIk) to form a mixture of the corresponding compounds of Formula (I) and (II) wherein R ^{1 is} selected from -OH, -OA, -A, -C (O) -A or SO ₂ -A. When reacting a mixture in Scheme 9 or 10, the resulting mixture of compounds of formula (I) and (II) is preferably separated according to known methods.

Schema 11 Compounds of formula (I) in which n is 1 and R ^{2 is} selected from the group consisting of halogen, cyano, aryl, heteroaryl, -SO ₂ -NH ₂ , -SO ₂ -NH (alkyl) and -SO ₂ -N (alkyl) ₂ , and in which the R ² group is attached to the carbon atom adjacent to the N atom of the E ring, can be prepared according to the procedure outlined in Scheme 11.

Scheme 11

Accordingly, a suitably substituted compound of formula (XXX) wherein PG ^{2 is} a suitable protecting group is reacted with a halide source such as iodine, bromine, NIS, NBS and the like in the presence of a base such as LDA, LiHMDS, t -BuOK and the like, in an organic solvent such as THF, diethyl ether, dioxolane and the like, to provide the corresponding compound of formula (XXXI) wherein X is the corresponding halogen (when the halide source is, for example, iodine or NIS is, then X is -I; if the halide source is bromine, NBS then X is -Br).

The compound of formula (XXXI) is reacted with a coupling agent such as CuCN and the like, optionally in the presence of a base such as diethylpropylamine, N-methylpyrrolidone and the like, in an organic solvent such as THF, DMF, DMSO and the like to provide the corresponding compound of formula (XXXVI), from which the protecting group is then removed by known methods to yield the corresponding compound of formula (Iq) wherein the R ² group is the CN group.

Alternatively, the compound of formula (XXXI) is reacted with CO in the presence of a catalyst such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd ₂ (dba) ₃ and the like in the presence of a base such as Et ₃ N, Bu ₃ N, K ₂ CO ₃ and the like, in the presence of a ligand such as DPPP, DPPE, Ph ₃ P, BINAP and the like, and then treated with a trapping agent such as H ₂ O or an alcohol of the formula a -OH such as MeOH, t-BuOH, phenol and the like, in an organic solvent such as toluene, dioxolane, DMF and the like, to afford the corresponding compound of formula (XXXVI), then by known methods the protecting group is cleaved to provide the corresponding compound of formula (Iq) wherein the R ² group is carboxy (when the scavenger is H ₂ O) or -C (O) -OA (when the scavenger is an alcohol) ,

Alternatively, the compound of formula (XXXI) is reacted with an appropriately substituted organometallic agent, such as an aryl or heteroaryl Grignard (a compound of formula (aryl or heteroaryl) -Mg halogen), an appropriately substituted stannyl group (a compound of formula (Aryl or heteroaryl) -Sn- (alkyl) ₃ ), an appropriately substituted boronic acid (a compound of the formula (aryl or heteroaryl) -B (OH) ₂ ) or a suitably substituted boronic ester (a compound of the formula (aryl or heteroaryl) -B (O-alkyl) ₂ ) and the like, in the presence of a catalyst such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd ₂ (dba) ₃ and the like, a base such as Et ₃ N, Bu ₃ N, K ₂ CO ₃ and the like, of a ligand such as DPPP, DPPE, Ph ₃ P, BINAP and the like, in an organic solvent such as toluene, dioxolane, DMF and the like, to give the corresponding To provide compound of formula (XXXVI), from which then by known methods the Cleaved to give the corresponding compound of formula (Iq), wherein the R ² group is aryl or heteroaryl.

Alternatively, the compound of formula (XXXI) is reacted with an appropriately substituted nitrogen-containing compound in the presence of a catalyst such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd ₂ (dba) ₃ and the like, a base such as such as t-BuONa, K ₃ PO ₄ , Cs ₂ CO ₃ , K ₂ CO ₃ and the like, a ligand such as DPPP, DPPE, Ph ₃ P, BINAP and the like, in an organic solvent such as toluene, dioxolane, DMF and the like, to provide the corresponding compound of formula (XXXVI), from which the protecting group is then removed by known methods to yield the corresponding compound of formula (Iq) wherein the R ² group is selected from Amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.

One skilled in the art will recognize that compounds of formula (I) wherein R ^{2 is} -SO ₂ -NH ₂ , -SO ₂ -NH (alkyl), or -SO ₂ -N (alkyl) ₂ can be prepared in a similar manner by reacting an appropriately substituted compound of formula (XXX) with chlorosulfonic acid in an organic solvent such as THF, diethyl ether, DCM, DMF, and the like, and then displacing the chlorine atom by quenching with an appropriately substituted amine.

worin X das entsprechende Halogen ist (wenn zum Beispiel die Halogenid-Quelle Iod oder NIS ist, dann ist X -I; wenn die Halogenid-Quelle Brom, NBS ist, dann ist X -Br). Die Verbindung von Formel (XXXII) wird dann gemäß dem oben umrissenen Verfahren umgesetzt, um das Halogenatom durch die gewünschte R²-Gruppe zu verdrängen.Compounds of formula (I) in which n is 1 and R ^{2 is} selected from the group consisting of halogen, cyano, aryl, heteroaryl, -SO ₂ -NH ₂ , -SO ₂ -NH (alkyl) and -SO ₂ -N (alkyl) ₂ , and in which the R ² group is attached to the carbon atom one carbon atom away from the N atom of the E ring, can similarly be prepared according to the procedure outlined in Scheme 11. In particular, the compound of formula (XXX) is reacted with a halide source such as iodine, bromine, NIS, NBS and the like in an organic solvent such as THF, diethyl ether, dioxolane and the like to give the corresponding compound of formula (XXXII)

where X is the corresponding halogen (for example, if the halide source is iodine or NIS then X is -I; if the halide source is bromine, NBS then X is -Br). The compound of formula (XXXII) is then reacted according to the procedure outlined above to displace the halogen atom by the desired R ² group.

Schema 12 Compounds of formula (I) wherein n is 1 and R ^{2 is} selected from the group consisting of -OH, -OA, -SA, -SO-A or SO ₂ -A can be prepared according to the procedure outlined in Scheme 12 getting produced.

Scheme 12

Accordingly, an appropriately substituted compound of formula (XXXI), wherein PG ^{2 is} a suitable protecting group and X is Cl, Br or I, is reacted with a coupling agent such as CuI, NiBr and the like in the presence of an appropriately substituted alcohol, a compound of the formula A-OH, or a suitably substituted compound of the formula A-SH in an organic solvent such as THF, DMF, toluene, dioxolane and the like, optionally in the presence of a catalyst such as Pd (OAc) ₂ , Pd (PPh ₃ ) ₂ Cl ₂ , Pd ₂ (dba) ₃ and the like, to provide the corresponding compound of formula (XXXIII) wherein R ^{2 is} -OA and -SA, respectively.

When R ² in the compound of formula (XXXIII) is -SA, the compound of formula (XXXIII) may optionally be treated with an oxidizing agent such as oxone, mCPBA, H ₂ O ₂ and the like in a solvent such as MeOH, THF , H ₂ O and the like, to provide the corresponding compound in which the R ² group is selected from -SO-A or -SO ₂ -A.

From the compound of formula (XXXIII) is the protecting group with known Methods cleaved off to the corresponding compound of formula (Ir) to deliver.

und Ersatz der Verbindung von Formel (XXXI) in Schema 12 durch eine geeignet substituierte Verbindung von Formel (XXXV)

One skilled in the art will recognize that the methods outlined in Schemes 11 and 12 can be similarly applied to the preparation of compounds of formula (II) by replacing the compound of formula (XXX) in Scheme 11 with an appropriately substituted compound of Formula (XXXIV)

and replacing the compound of formula (XXXI) in scheme 12 with an appropriately substituted compound of formula (XXXV)

One Those skilled in the art will recognize that the methods in Schemes 11 and 12 in similar Way can be applied to provide a mixture of compounds of formula (I) and (II), by using a mixture of suitably substituted compounds of Formula (XXX) and (XXXIV) in Scheme 11 and a mixture of suitably substituted compounds of formula (XXXI) and (XXXV) in Scheme 12. Where the procedures are applied to a mixture of compounds of formula (I) and (II), the Compounds of formula (I) and (II) preferably with known Methods separated.

One One skilled in the art will further recognize that in the schemes described herein Outlined procedures described in each combination are performed can, the one compound of formula (I) or (II) with the desired Will provide substituent groups.

Where the compounds according to this Invention have at least one chiral center, they can accordingly as enantiomers exist. Where the compounds have two or more chiral centers, can you additionally exist as diastereomers. One should understand that all such Isomers and mixtures thereof within the scope of the present invention Invention are included. Furthermore could some of the crystalline forms for the compounds exist as polymorphs, and these are supposed to be such may be included in the present invention. In addition, some can the compounds solvates with water (i.e., hydrates) or conventional organic solvents and such solvates should also be within the scope of this Be included invention.

Where the processes for the preparation of the compounds according to the invention lead to mixtures of stereoisomers, these isomers by conventional Techniques, such as preparative Chromatography, to be separated. The connections can be made in racemic form, or individual enantiomers can either by enantiospecific synthesis or by separation become. The connections can for example, by standard techniques in their component enantiomers such as the formation of diastereomeric pairs by salification with an optically active acid such as (-) - di-p-toluenoyl-1-tartaric acid and / or (+) - di-p-toluenyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The connections can also by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary, be separated. Alternatively you can the compounds are separated using a chiral HPLC column.

During all Process for the preparation of the compounds of the present invention may be necessary and / or desirable be to protect sensitive or reactive groups on any of the affected molecules. This can by means of conventional Protective groups can be achieved, such as those in "Protective Groups in Organic Chemistry ", Ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, "Protective Groups in Organic Synthesis ", John Wiley & Sons, 1991, are described. The protecting groups may be in any suitable subsequent Stage using methods known in the art be split off.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily convertible into the required compound in vivo. Thus, in the treatment methods of the present invention, the term "administering" is intended to refer to the treatment of the various described disorders with the specifically disclosed compound or with a compound which may not be specifically disclosed, but in vivo after administration to the patient Conventional methods for the selection and preparation of suitable prodrug derivatives are described, for example, in "De Sign of Prodrugs, eds. H. Bundgaard, Elsevier, 1985.

The usefulness the compounds of the present invention to interfere with treated by an estrogen receptor, can according to the procedures determined in Examples 18, 19, 20 and 21 herein are described.

The The present invention therefore provides a method of treatment of disorders prepared by an estrogen receptor a person in need of it, the administration of a the compounds, as defined herein, in an amount, which is effective to said malfunction to treat. The connection can be made to a patient via any one usual Administration route, including, but not limited to, intravenously, oral, subcutaneous, intramuscular, intradermally and parenterally. The amount of compound that is effective for the treatment of a disorder that is mediated by an estrogen receptor lies between 0.01 mg per kg and 20 mg per kg of body weight.

The The present invention also provides pharmaceutical compositions to disposal, the one or more compounds of this invention together with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms, such as tablets, Pills, capsules, powders, granules, sterile parenteral solutions or suspensions, aerosol or liquid dosing sprays, drops, Ampoules, autoinjector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration or for Administration by inhalation or insufflation. Alternatively, you can the composition in a for once a week or once-monthly administration of appropriate form; for example, an insoluble one Salt of the active compound, such as the decanoate salt, to a depot preparation for intramuscular injection to deliver. For the preparation of solid compositions, such as tablets, becomes the main one active ingredient with a pharmaceutical carrier mixed, z. B. conventional Tabletting agents such as corn starch, lactose, sucrose, sorbitol, Talc, stearic acid, Magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical Diluents, z. Water to form a solid preformulation composition, a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. If referring to this preformulation composition as homogeneous, It is meant that the active ingredient is even in the throughout the composition is distributed, so the composition. easily into equally effective dosage forms, such as tablets, Pills and capsules, can be divided. This solid preformulation composition is then subdivided into unit dosage forms of the type described above, from 5 to about 1000 mg of the active ingredient of the present invention Invention included. The tablets or pills of the novel composition can coated or otherwise compounded to form a dosage form to provide the advantage of prolonged action. The For example, a tablet or pill may have an inner dosage and an external dosage component comprise, the latter being in the form of an envelope over the former. The two Components can be separated by an enteric coating which serves to to resist disintegration in the stomach, and allow the inner component intact into the duodenum passes or delayed in the release becomes. A variety of materials may be suitable for such enteric-coated Layers or coatings are used, such materials a series of polymeric acids lock in, with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid Forms in which the novel compositions of the present Invention for oral administration or incorporated by injection can be shut down aqueous Solutions, suitable flavored syrups, aqueous or oily suspensions and flavored emulsions with edible oils, such as about cottonseed oil, Sesame oil, Coconut oil or peanut oil, as well Elixirs and similar pharmaceutical vehicle. Suitable dispersing or suspending agents for aqueous suspensions shut down synthetic and natural Gums, such as gum tragacanth, acacia, alginate, dextran, Sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The method of treating a disorder mediated by an estrogen receptor described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 5 mg and 1000 mg, preferably about 10 to 500 mg, of the compound and may be brought into any suitable form for the selected mode of administration. Carriers include necessary and inert excipients, including, but not limited to, excipients, suspending agents, lubricants, flavoring agents, sweeteners, preservatives, colors and coatings. Composition suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules and powders, and liquid forms such as solutions. Syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

advantageously, can Compounds of the present invention in a single daily Dose, or the total daily dosage may be in divided doses of two, three or four times a day become. moreover can Compounds of the present invention in intranasal form via topical Use of suitable intranasal vehicles or via transdermal skin patches, which are well known to those of ordinary skill in the art, be administered. To be in the form of a transdermal delivery system to be administered Of course, the dosage administration will take place continuously intermittently during of the dosage regimen.

For oral Administration in the form of a tablet or capsule may be the active Drug component, for example, with an oral, non-toxic, pharmaceutically acceptable, inert carrier are combined, such as ethanol, glycerol, water and the like. moreover can, if desired or necessary, suitable binders, lubricants, disintegrants and colorants be incorporated into the mixture. Close suitable binders without restriction Strength, Gelatin, natural Sugars, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia gum, tragacanth gum or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, Sodium acetate, sodium chloride and the like. disintegrators shut down, without restriction, Strength, Methylcellulose, agar, bentonite, xanthan gum and the like.

The liquid Can shape suspending or dispersing agents mixed with suitable flavoring agents lock in, such as the synthetic and natural gums, for example Gum tragacanth, gum acacia, methyl cellulose and the like. For parenteral Administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives used when intravenous Administration desired is.

The Compound of the present invention may also be administered in the form of liposome delivery systems are, such as small unilamellar vesicles, large unilamellar Vesicles and multilamellar vesicles. Liposomes can take off a variety of phospholipids are formed, such as cholesterol, Stearylamine or phosphatidylcholines.

links of the present invention also by the use of monoclonal antibodies as an individual carrier the the connecting molecules coupled, fed become. The compounds of the present invention may also with soluble Polymers are coupled as targetable drug carriers. Such Polymers can Polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol, Polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine, substituted with palmitoyl radical. Moreover, the compounds of the present Invention coupled to a class of biodegradable polymers become useful are in order to achieve controlled release of a drug, for example polylactic acid, Polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, Polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic Block copolymers of hydrogels.

The Compounds of this invention can in each of the above compositions and according to in State of the art are administered to established dosage regimes, whenever treatment of a disorder, which is mediated by an estrogen receptor required is.

The daily Dosage of the products can over a wide range of 5 to 1,000 mg per adult human be varied per day. For Oral administration, the compositions are preferably in of the form of tablets being 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of the active ingredient included, for the symptomatic adjustment of the dosage to be treated Patients. An effective amount of the drug will become common at a dosage level of about 0.01 mg / kg to about 20 mg / kg body weight fed per day. Preferably the range of about 0.1 mg / kg to about 10 mg / kg of body weight per day and in particular from about 0.5 mg / kg to about 10 mg / kg of body weight per day. The connections can be administered in a regimen of 1 to 4 times a day.

optimal can be administered doses easily determined by the professionals and will be with the particular used, the mode of administration, the strength of the Preparation and the progress of the disease state vary. additionally will be factors associated with the particular patient being treated related, including Patient age, weight, nutrition and administration timing, lead to the need to adjust dosages.

The following examples are given to aid in the understanding of the invention, and are not intended and should not be so so. are considered to limit in any way the invention set forth in the claims which follow hereafter. example 1

CF ₃ (CF ₂ ) ₃ SO ₂ F (27.7 mmol, 4.97 ml) was added dropwise via syringe to a solution of estrone (18.5 mmol, 5.0 g) and TEA (27.7 mmol, 3, 90 ml) in CH ₂ Cl ₂ (100 ml) at 0 ° C. The reaction mixture was warmed slowly to room temperature over 2 h. The solution was then washed with saturated NaHCO ₃ and brine, then dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to afford a white solid. The white solid was purified by flash chromatography using 4: 1 hexanes / EtOAc to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.35 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.0 Hz, 1H), 7.01 (s, 1H), 2.95 (m, J = 4.1 Hz, 2H), 2.42 (dd, J = 18.0, 8.8 Hz, 1H), 2.38 (m, 1H), 2, 30 (m, 1H), 2.15 (dd, J = 17.6, 8.8 Hz, 1H), 2.10 ~ 1.99 (m, 3H), 1.77 ~ 1.51 (m, 6H), 0.98 (s, 3H).
MS (m / z) MW (551). Example 2

A three-necked flask was charged with Pd (OAc) ₂ (0.0182 mmol, 4.1 mg), BINAP (0.02 mmol, 12 mg) and NaO-t-Bu (1.274 mmol, 122 mg). The reaction mixture was stirred in toluene (20 ml) for 10 min at 80 ° C. A mixture of NH ₂ CH ₂ CH (OCH ₂ CH ₃ ) ₂ (1.092 mmol, 159 μl) and the compound prepared as in Example 1 (0.91 mmol, 500 mg) in toluene (2 ml) was then slowly added dropwise Syringe added to the reaction mixture. After addition, the mixture was heated at 80 ° C with stirring for 2 h. The reaction mixture was cooled to room temperature. Et ₂ O and water were added and the solution was partitioned between Et ₂ O and water. The Et ₂ O layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated to afford the title compound as a crude solid. The crude product was purified by column chromatography using 4: 1 hexanes / EtOAc to afford the title compound as a colorless oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.12 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 8.8 Hz, 1H), 6.38 (s, 1H), 4.68 (t, J = 6.0 Hz, 1H), 3.80 (br, s, 1H), 3.75 (m, 2H), 3.60 (m, 2H), 3, 22 (d, J = 6.0 Hz, 2H), 2.91 (m, 2H), 2.50 (dd, J = 18.0, 8.8 Hz, 1H), 2.42 (m, 1H ), 2.35 (m, 1H), 2.20 (m, 1H), 2.15, 1.94 (m, 3H), 1.72 ~ 1.38 (m, 6H), 1.25 (t , J = 7.6 Hz, 6H), 0.98 (s, 3H).
MS (m / z) M + Na (408), MW ^- (384). Example 3

Pyridine (5.52 mmol, 446 μl) was added dropwise via syringe to a solution of the compound prepared as in Example 2 (3.68 mmol, 1.417 g) in CH ₂ Cl ₂ (50 ml) at 0 ° C, followed by the addition of CH ₃ SO ₂ Cl (4.42 mmol, 342 μl). The reaction mixture was then stirred and warmed to room temperature over 2 hours. The solution was partitioned between CH ₂ Cl ₂ and saturated NaHCO ₃ . The organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a colorless oil. The product was sufficiently pure to be used in the next step without further purification.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.28 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 7.10 (s, 1H), 4.61 (t, J = 5.5 Hz, 1H), 3.75 (d, J = 5.5 Hz, 2H), 3.62 (m, 2H), 3.54 (m, 2H), 3.05 (s, 3H), 2.91 (m, 1H), 2.55 (m, 1H), 2.40 (m, 1H), 2.22 (dd, J = 17.5 , 8.0 Hz, 1H), 2.15 ~ 1.95 (m, 4H), 1.75 ~ 1.38 (m, 6H), 1.15 (t, J = 7.5 Hz, 6H) , 0.94 (s, 3H).
MS (m / z) MH ⁺ (464). Example 4 - (Compounds # 1 and # 2)

A mixture of the compound prepared in Example 2 (887 mg, 1.916 mmol) in toluene (15 mL) was treated with PPA (~ 1.0 g). The reaction mixture was then heated at reflux for 2 h. The reaction mixture was then cooled to room temperature, the solution was washed with water, saturated NaHCO ₃ and brine and then dried over anhydrous Na ₂ SO ₄ . The resulting salt was filtered off and the solution was concentrated to provide a mixture of the title compounds as a clean oil. The oil was purified by chromatography (Biotage) using CH ₂ Cl ₂ as eluent to afford the title compounds.

(E4a):

• ¹ H-NMR (300 MHz, CDCl ₃₎ δ 7.68 (s, 1H), 7.55 (s, 1H), 7.36 (d, k J = 3.2 Hz, 1H), 6.67 (d, J = 3.2 Hz, 1H), 3.20 ~ 3.00 (m, 2H), 3.10 (s, 3H), 2.62 ~ 2.50 (m, 2H), 2, 45 (m, 1H), 2.32 ~ 2.01 (m, 4H), 1.75 ~ 1.45 (m, 6H), 0.98 (s, 3H);
• MS (m / z) MH ⁺ (373).

(E4b):

• ¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.75 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.39 (d, J = 7.5Hz, 1H), 6.70 (d, J = 3.0Hz, 1H), 3.21 ~ 3.02 (m, 2H), 3.11 (s, 3H), 2, 60 ~ 2.38 (m, 3H), 2.28 ~ 1.98 (m, 4H), 1.83 ~ 1.48 (m, 6H), 0.98 (s, 3H).
• MS (m / z) MH ⁺ (373).

Example 5 - (compound # 3)

A mixture of Compound # 1, prepared as in Example 3, (48 mg, 0.13 mmol) in 5% KOH in EtOH solution (1 mL) was heated at reflux for 6 h. The reaction mixture was cooled to room temperature therein, the solvent removed in vacuo and the residue partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layer was then washed with saturated NH ₄ Cl, water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using CH ₂ Cl _{2 to} afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 8.02 (br, s, 1H), 7.58 (s, 1H), 7.18 (s, 1H), 7.16 (d, J = 3 , 0 Hz, 1H), 6.45 (d, J = 4.5 Hz, 1H), 3.05 (m, J = 6.0 Hz, 2H), 2.58 ~ 2.35 (m, 3H ), 2.25~1.97 (m, 414), 1.78~1.45 (m, 6H), 0.92 (s, 3H).
MS (m / z) M + Na (316), MH ⁺ (294). Example 6 - (compound # 4)

Compound # 2, prepared as in Example 3, (54 mg, 0.145 mmol) in 5% KOH in EtOH solution (1 mL) was heated at reflux for 6 h. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was partitioned between EtOAc and water. The aqueous layer was extracted three times with EtOAc. The combined organic layer was then washed with sat. Na ₄ Cl, water and brine, then dried over anhydrous NH ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using CH ₂ Cl _{2 to} afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.15 (br, s, 1H), 7.24 (s, 1H), 7.22 (s, 1H), 7.20 (d, J 3, 0 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 3.25 ~ 3.01 (m, 2H), 2.65 ~ 2.38 (m, 3H), 2, 25 ~ 1.90 (m, 4H), 1.82 ~ 1.48 (m, 6H), 0.92 (s, 3H).
MS (m / z) MH ⁺ (294). Example 7 - (compound # 7)

NaBH ₄ (1.56 mmol, 59 mg) was prepared in one portion to a mixture of Compound # 1 as in Example 3, (58 mg, 0.156 mmol) in MeOH (2 mL) at 0 ° C. The reaction mixture was mentioned to room temperature over 10 minutes. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using 3: 1 hexanes / EtOAc to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 7.65 (s, 1H), 7.59 (s, 1H), 7.32 (d, J = 4.0 Hz, 1H), 6.65 ( d, J = 4.0 Hz, 1H), 3.78 (t, J = 9.0 Hz, 1H), 3.10 (s, 3H), 3.12 ~ 3.01 (m, 2H), 2.82~2.78 (m, 1H), 2.41~2.22 (m, 2H), 2.20~2.11 (m, 1H), 1.98~1.92 (m, 1H ), 1.85 ~ 1.60 (m, 2H), 1.59 ~ 1.25 (m, 6H), 0.85 (s, 3H).
MS (m / z) MH ⁺ (375). Example 8 - (compound # 5)

NaBH ₄ (2.13 mmol, 81 mg) was added in one portion to a mixture of Compound # 2, prepared as in Example 3, (79 mg, 0.213 mmol) in MeOH (3 mL) at 0 ° C. The reaction mixture was warmed to room temperature over 10 minutes. The solvent was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography purification 3: 1 hexanes / EtOAc to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 7.66 (d, J = 9.5 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 6.65 (d, J = 3.5 Hz, 1H), 3.70 (t, J = 9.0 Hz, 1H), 3.05 (s, 3H) , 3.10~2.85 (m, 2H), 2.55~2.25 (m, 3H), 2.15~2.02 (m, 2H), 2.00~1.85 (m, 2H), 1.80 ~ 1.42 (m, 6H), 0.90 (s, 3H).
MS (m / z) MH ⁺ (375). Example 9 - (compound # 8)

A mixture of Compound # 7, prepared as in Example 7, (51 mg, 0.137 mmol) in 5% KOH in EtOH solution (2 mL) was refluxed for 2 h. The reaction mixture was then cooled to room temperature, the solvent was removed in vacuo, and the residue was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with saturated NH ₄ Cl, water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using 2: 1 hexanes / EtOAc to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.01 (br s, 1H), 7.68 (s, 1H), 7.14 (s, 1H), 7.12 (d, J = 3, 5 Hz, 1H), 6.45 (d, J = 3.5 Hz, 1H), 3.75 (t, J = 8.5 Hz, 1H), 3.05 ~ 2.95 (m, 2H) , 2.52 (m, 1H), 2.43 (m, 1H), 2.15 (m, 1H), 2.05~1.88 (m, 2H), 1.80~1.58 (m , 2H), 1.55 ~ 1.28 (m, 6H), 0.85 (s, 3H).
MS (m / z) M + Na (318), MH ⁺ (296). Example 10 - (compound # 6)

Compound # 5, prepared as in Example 8, (71 mg, 0.190 mmol) in 5% KOH in EtOH solution (2 mL) was refluxed for 2 h. After the reaction was cooled to room temperature, the solution was removed in vacuo and the residue was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with saturated NH ₄ Cl, water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to produce a clean solid. The solid was purified by flash chromatography using 2: 1 hexanes / EtOAc to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.05 (br s, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 7.12 (d, J = 3, 5Hz, 1H), 6.45 (d, J = 3.5Hz, 1H), 4.65 (t, J = 9.5Hz, 1H), 3.10 ~ 2.90 (m, 2H) , 2.40 ~ 2.28 (m, 2H), 2.20 ~ 2.08 (m, 1H), 1.98 (m, 1H), 1.85 (m, 1H), 1.78 (m , 1H), 1.65 (m, 1H), 1.60 ~ 1.28 (m, 6H), 0.85 (s, 3H).
MS (m / z) M + Na (318), MW (294). Example 11 - (compound # 10)

Lithium acetylide-ethylenediamine complex (46 mg, 0.523 mmol) was added to a mixture of Compound # 1, prepared as in Example 4, (45 mg, 0.153 mmol) in dry dioxane (1 mL) and DMSO (1 mL) at room temperature , The reaction mixture was stirred for 1 h. The solvent was removed and then EtOAc and water were added. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude yellow oil. The oil was purified by flash chromatography using 2: 1 hexanes / EtOAc to afford the title compound as a yellowish oil.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 8.00 (br, s, 1H), 7.60 (s, 1H), 7.15 (s, 1H), 7.12 (d, J = 2 , 0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 2.98 ~ 2.92 (m, 2H), 2.95 (s, 1H), 2.82 ~ 2 , 68 (m, 1H), 2.50 ~ 2.25 (m, 2H), 2.21 ~ 2.05 (m, 1H), 2.01 ~ 1.85 (m, 1H), 1.78 ~ 1.52 (m, 2H), 1.50 ~ 1.25 (m, 6H), 0.80 (s, 3H).
MS (m / z) MH ⁺ (320). Example 12 - (compound # 9)

Lithium acetylide-ethylenediamine complex (69 mg, 0.784 mmol) was added to a mixture of compound # 2, prepared as in Example 4, (67 mg, 0.229 mmol) in dry dioxane (1 mL) and DMSO (1 mL) at room temperature , The reaction mixture was stirred for 1 h. The solvent was removed and then EtOAc and water were added. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude yellow oil. The oil was purified by flash chromatography using 2: 1 hexanes / EtOAc to afford the title compound as a yellowish oil.
¹ H-NMR (300 MHz, CDCl ₃ ) δ 8.05 (br s, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.15 (d, J = 3, 0 Hz, 1H), 6.48 (d, J = 3.0 Hz, 1H), 3.10 ~ 2.95 (m, 2H), 2.60 (s, 1H), 2.52 ~ 2, 25 (m, 4H), 2.10 ~ 1.85 (m, 2H), 1.80 ~ 1.65 (m, 2H), 1.55 ~ 1.32 (m, 5H), 0.88 (s, 3H).
MS (m / z) MH ⁺ (320). Example 13 - (compound # 12)

Pyridine (0.141 mmol, 12 μl) and a catalytic amount of DMAP (1 mg) were added to a mixture of 12a-methyl-1,2,3,3a, 3b, 4,5,7,10b, 11,12,12a- dodecahydro-7-aza-dicyclopenta [a, h] phenanthren-1-ol, a known compound, (38 mg, 0.129 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C, followed by the addition of valeric acid chloride (0.129 ml, 16 μl). The reaction mixture was stirred at 0 ° C for 2 h and then warmed to room temperature. The mixture was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with saturated NH ₄ Cl, water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using 3: 1 hexanes / EtOAc to afford the title compound as a yellow solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 7.92 (br, s, 1H), 7.68 (s, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.45 (s, 1H), 4.72 (t, J = 8.5Hz, 1H), 3.05 (m, 2H), 2.48 ~ 2.40 (m, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.30 ~ 2.22 (m, 1H), 2.00 ~ 1.85 (d, J = 9.5 Hz, 2H), 1.80 ~ 1.72 (m, 1H), 1.70 ~ 1.52 (m, 1H), 1.65 (t, J = 7.5Hz, 2H), 1.50 ~ 1.25 (m, 6H) , 1.36 (m, J = 7.5 Hz, 2H), 0.95 (t, J = 7.5 Hz, 3H), 0.90 (s, 3H).
MS (m / z) MH ⁺ (381). Example 14 - (compound # 11)

Pyridine (0.123 mmol, 10 μl) and a catalytic amount of DMAP (1 mg) were added to a mixture of 7a-methyl-3,5b, 6,7,7a, 8,9,10,10a, 10b, 11,12- dodecahydro-3-aza-dicyclopenta [a, 1] -phenanthren-8-ol, a known compound, (33 mg, 0.112 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C, followed by the addition of valeryl chloride (0.123 mmol, 27 μl). The reaction mixture was stirred at 0 ° C for 2 h and then warmed to room temperature. The mixture was partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with saturated NH ₄ Cl, water and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography purification using 3: 1 hexanes / EtOAc to afford the title compound as a yellow solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 8.12 (s, br, 1H), 7.25 (d, J = 3.0 Hz, 1H), 7.22 (d, J = 3.0 Hz, 1H), 7.22 (d, J = 3.0 Hz, 1H), 7.20 (d, J = 3.5 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 4.75 (t, J = 8.5Hz, 1H), 3.10~2.98 (m, 2H), 2.48~2.40 (m, 2H), 2.33 (t , J = 8.0 Hz, 2H), 2.30 ~ 2.20 (m, 1H), 2.11 ~ 2.02 (m, 1H), 2.00 ~ 1.85 (m, 1H), 1.80 ~ 1.66 (m, 1H), 1.65 (t, J = 8.0 Hz, 2H), 1.60 ~ 1.28 (m, 5H), 1.40 (m, J = 8.0 Hz, 2H), 0.95 (t, J = 8.5 Hz, 3H), 0.85 (s, 3H).
MS (m / z) MH ⁺ (381). Example 15 - (Compound # 13).

Pyridine (0.370 mmol, 30 μl) and a catalytic amount of DMAP (10 mg) were added to a mixture of 12a-methyl-1,2,3,3a, 3b, 4,5,7,10b, 11,12,12a- dodecahydro-7-aza-dicyclopenta [a, h] phenanthren-1-ol, a known compound, (68 mg, 0.231 mmol) in CH ₂ Cl ₂ (2 mL) at 0 ° C, followed by the addition of succinic anhydride (0.346 mmol, 35 mg). The reaction mixture was stirred at 0 ° C for 2 h and at room temperature overnight. The mixture was then partitioned between CH ₂ Cl ₂ and water. The aqueous layer was extracted twice with CH ₂ Cl ₂ . The combined organic layer was then washed with saturated Na ₄ Cl, water and brine, then dried over anhydrous NH ₂ SO ₄ , filtered and concentrated to afford the title compound as a crude solid. The solid was purified by flash chromatography using 2: 1 hexanes / EtOAc to afford the title compound as a yellow solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 7.95 (br, s, 1H), 7.65 (s, 1H), 7.12 (s, 2H), 6.48 (s, 1H), 4.72 (t, J = 7.0 Hz, 1H), 3.10 (m, 2H), 2.80 ~ 2.58 (m, 4H), 2.50 ~ 2.32 (m, 2H) , 2.30~2.15 (m, 1H), 1.95~1.85 (d, J = 9.0 Hz, 2H), 1.80 (m, 1H), 1.75~1.50 (m, 2H), 1.48 ~ 1.30 (m, 5H), 0.85 (s, 3H).
MS (m / z) MH ⁺ (396), MW (394). Example 16 - (compound # 14

A solution of NaOH (0.0572 mmol, 1.0 N in THF solution) was added to compound # 13, prepared as in Example 15, (26 mg, 0.066 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo to afford the title compound as a white solid. The solid was dried at 50 ° C under vacuum for 10 h to afford the title compound as a white solid.
¹ H-NMR (300 MHz, CDCl ₃₎ δ 7.41 (s, 1H), 7.12 (d, J = 3.0 Hz, 1H), 7.08 (s, 1H), 6.35 ( d, J = 3.0 Hz, 1H), 4.68 (t, J = 8.5 Hz, 1H), 2.98 (m, 2H), 2.70 ~ 2.48 (m, 4H), 2.40~2.22 (m, 1H9, 2.32~2.18 (m, 1H), 2.20~2.12 (m, 1H), 1.98~1.85 (m, 2H) , 1.80 ~ 1.62 (m, 1H), 1.60 ~ 1.48 (m, 1H), 1.48 ~ 1.25 (m, 6H), 0.90 (s, 3H). Example 17 - (connection # 15)

To a vigorously stirred solution of 3-amino-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydrocyclopenta [a] phenanthren-17-one (101 mg, 0.37 mmol) in dichloromethane (5 mL) at -65 ° C was added dropwise a solution of t-BuOCl (0.37 mmol, 40 mg) in DCM (1 mL). After 5 min, 1,1-dimethoxy-2-methylsulfanylethane (0.37 mmol, 50 μl) dissolved in DCM (0.5 ml) was added to the reaction, followed by the addition of Et ₃ N (0.37 mmol , 52 μl). The reaction mixture was then stirred for 1 h. To the reacted mixture was added DCM (10 ml), the resulting mixture was washed with 1N HCl, saturated NaHCO ₃ and brine, then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford a crude product. The crude material was purified using column chromatography and a 3: 1 hexanes: EtOAc mixture as eluant to afford the title compound as a pale solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (br s, ¹ H), 7.20 (d, J = 8.5 Hz, ¹ H), 7.15 (d, J = 8.5 Hz , 1H), 6.52 (d, J = 2.5 Hz, 1H), 3.25-3.01 (m, 2H), 2.65-2.38 (m, 3H), 2.50 ( s, 3H), 2.25 1.90 (m, 4H), 1.82-1.48 (m, 6H), 0.92 (s, 3H).
MS (m / z) MH ⁺ (340).

Example 18

Estrogen receptor α Flash Plate test

This Test monitored the binding of radiolabelled estrogen to the estrogen receptor. He will performed on a BioMek 2000 (Beckman). Plates are in one scintillation (Packard TopCount), with decreased counts are an indication of binding of a compound by the receptor. The test is done according to the procedure carried out, which is described by Allan et al., Anal. Biochem. (1999), 275 (2), 243-247.

At Day one was 100 μl Estrogen Screening Buffer (ESB, Panvera) containing 5 mM dithiothreitol (DTT, Panvera), 0.5 μg monoclonal mouse anti-estrogen receptor antibody (SRA-1010, Stress gene) and 50 ng purified human estrogen receptor α (nER-α, Panvera), added to each well of a 96-well FlashPlate Plus plate, cross-linked with goat anti-mouse antibodies (NEN Life Sciences). The plate was sealed and stored at 4 ° C overnight incubated.

At Day two, each well was washed three times with 200 μl of PBS, pH 7.2, at room temperature washed. To each well was then added 98 μl of radiolabelled estrogen (0.5 nM, which is 6 nCi for a charge of 120 Ci / mmol, Amersham) diluted in ESB, and 5 mM dithiothreitol (DTT). To the individual wells then 2.5 μl Test compound added, diluted in 30% (v / v) dimethyl sulfoxide / 50 mM HEPES, pH 7.5. The wells were mixed three times by suction, the plate sealed and at Room temperature for incubated for one hour. The wells were then left for 1 min in a TopCount scintillation counter (Packard).

Example 19

Estrogen receptor β-fluorescence polarization assay

This Test monitored the binding of a fluorescent analog of estrogen (Fluormone ES2, Panvera) to the estrogen receptor. Plates were in one Read fluorometer set to polarization mode can. A decrease in fluorescence relative to vehicle control is an indication of binding of a compound to the receptor.

It is crucial, the introduction of air bubbles in the reaction in each well of the 96-well plate throughout the process to avoid. (Break bubbles on the surface of the reaction the fluence, which affects the polarization reading.) It is but also crucial, the reaction components when added to the Well to mix well.

On Ice became a 2X standard mixture of Assay Buffer (Panvera), 10 nM DTT and 40 nM ES2 produced. On ice was also a 2X reaction mixture Assay Buffer (Panvera) and 20 nM Human Estrogen Receptor β (hER-β, Panvera) and 40 nM ES2.

dilutions of test compound were dissolved in 30% (v / v) dimethylsulfoxide / 50mM HEPES, pH 7.5. At this point, the dilutions were 40X of the final required concentration.

The Standard mix with 50 μl was then added to each well. The reaction mixture with 48 .mu.l was added to all wells. The compound dilution with 2.5 μl was added added to the appropriate wells. The reaction mixtures were mixed using a manual pipette, a roll made of aluminum foil adhesive cover, the plate was applied and the plate at room temperature for Incubated for 1 hour.

each Well on the plate was then read in a LjL analyst, with an excitation wavelength of 265 nm and an emission wavelength of 538.

Representative compounds of the present invention were tested for binding to the estrogen receptor α and estrogen receptor β according to the method described above, as described in Examples 18 and 19 above, with results as listed in Table 3. Table 3 ID no. ERα binding IC ₅₀ (μM) ERα at 1 μM% inhibition ERB binding IC ₅₀ (μM) ERβ at 1 μM% inhibition 1 11 6.2 2 45 27 3 2.2 > 10 4 1.4 0.61 6 0,042 0.091 7 19 14 8th 0,040 0.15 12 95 96 13 0.92 0.61 15 81 66

Example 20

MCF-7 cell proliferation assay

This Test was done according to the procedure carried out, described by Welshons, et al. (Breast Cancer Res. Treat. 1987, 10 (2), 169-75), with minor Modification.

Briefly, MCF-7 cells (from Dr. C. Jordan, Northwestern University) in phenol red-free RPMI 1640 medium (Gibco) in 10% FBS (Hyclone) supplemented with bovine insulin and nonessential amino acid (Sigma), held. The cells were initially treated with 4-hydroxyl tamoxifen (10 ^-8 M) and allowed to stand at 37 ° C for 24 hours. Following this incubation with tamoxifen, cells were treated with compounds at various concentrations.

Compounds to be tested in agonist mode were added to the culture medium at varying concentrations. Compounds to be treated in the antagonist mode were prepared in a similar manner, and 10 nM 17β-estradiol was also added to the culture medium. The cells were incubated for 24 hours at 37 ° C. Following this incubation, 0.1 μCi ¹⁴ C-thymidine (56 mCi / mmol, Amersham) was added to the culture medium and the cells were incubated for a further 24 hours at 37 ° C. The cells were then washed with Hank's buffered saline (HBSS) (Gibco) and counted with a scintillation counter. The increase in ¹⁴ C-thymidine in the compound-treated cells relative to the vehicle control cells was reported as a percentage increase in cell proliferation.

Example 21

alkaline Phosphatase test in human uterine lining Ishikawa cells This test was done according to the procedure carried out, described by Albert et al., Cancer Res. (9910), 50 (11), 330-6-10, with minor Modification.

Ishikawa cells (from ATCC) were dissolved in phenol red-free DMEM / F12 (1: 1) medium (Gibco), supplemented with 10% calf serum (Hyclone). 24 hours before testing, the medium was changed to DMEM / F12 (1: 1), Phenol red free, containing 2% calf serum.

Compounds to be tested in agonist mode were added to the culture medium at varying concentrations. Compounds to be treated in the antagonist mode were prepared in a similar manner and 10 nM 17β-estradiol was also added to the culture medium. The cells were then incubated at 37 ° C for 3 days. On the fourth day, the medium was removed, 1 volume of 1X Dilution Buffer (Clontech) was added to the well, followed by the addition of 1 volume of Assay Buffer (Clontech). The cells were then incubated at room temperature for 5 minutes. 1 volume of freshly prepared chemiluminescence buffer (1 volume of chemiluminescent substrate (CSPD) in 19 volumes of chemiluminescent enhancer with a final concentration of CSPD at 1.25 mM; Sigma Chemical Co.) was added. The cells were incubated at room temperature for 10 minutes and then quantitated on a luminometer. The increase in chemiluminescence over vehicle control was used to calculate the increase in alkaline phosphatase activity.

Representative compounds of the present invention were tested according to the method described in Examples 20 and 21 above, with results as listed in Table 4. Table 4 ID no. MCF7 (chest) EC ₅₀ (nM) Ishikawa (uterine lining) EC ₅₀ (nM) 3 240 1.9 4 280 1.8 6 2.9 0.21 8th 11 0.44 13 15 1.2

Example 22

When a specific embodiment of an oral composition will be 100 mg of Compound # 6, like in Example 10, formulated with sufficiently finely divided lactose, to provide a total of 580 to 590 mg to one Hard gel capsule size O too to fill.

Although the above description is the principles of the present invention teaches, with examples provided for illustrative purposes It will be understood that the practice of the invention is all common Variations, adaptations and / or modifications include, as they are within the scope of the following claims and their equivalents fall.

Claims (17)

Compound of formula (I)

wherein R ^{1 is} selected from the group consisting of hydrogen, hydroxy, A, -OA, C (O) -A and -SO ₂ -A; n is an integer from 0 to 2; Each R ² is independently selected from the group consisting of hydroxy, carboxy, halo, -A, -OA, -C (O) -A, -C (O) OA, amino, (C 1 -C 8) alkylamino, di - (C 1 -C 8) -alkylamino, cyano, aminocarbonyl, (C 1 -C 8) -alkylaminocarbonyl, di- (C 1 -C 8) -alkylaminocarbonyl, -SH, -SA, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (C 1 -C 8 -alkyl) and -SO ₂ -N (C 1 -C 8 -alkyl) ₂ ; m is an integer of 0 to 2; Each R ³ is independently selected from the group consisting of -A, -OA, -SA, -NH-A, -N (A) ₂ and -C (O) -A; p is an integer of 1 to 2; Each R ⁴ is independently selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, - (C 2 -C 8) -alkynyl-A, (C 2 -C 8) -alkynyl, - (C 2 -C8) alkynyl-A, -OA, -NH ₂ , NH (A), -N (A) ₂ , -N (A) -C (O) -A, -NH-C (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , C (O) -NH-A, -SO ₂ N (A) ₂ , -SO ₂ -NH (A), -SO ₂ -NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O) -A; alternatively, when p is 2, two R ⁴ groups may be taken together as oxo or = N (OH); q is an integer from 0 to 2; Each R ⁵ is independently selected from the group consisting of hydroxy, carboxy, halo, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 3 -C 8) cycloalkyl, and -C (O) -A; wherein the (C 1 -C 8) alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy or (C 1 -C 8) alkoxy; each A is independently selected from the group consisting of (C 1 -C 8) alkyl, aryl, aralkyl, (C 3 -C 8) cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, (C3-C8) -cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, (C1-C4) -alkyl, ( C 1 -C 8) -alkoxy, nitro, cyano, amino, (C 1 -C 4) -alkylamino or di- ((C 1 -C 4) -alkyl) -amino; wherein a heteroaryl is a five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom, which is selected from the group consisting of O, N and S, a heterocycloalkyl is a five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- to ten-membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, and an aryl is a carbocyclic aromatic group; or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that R ^{1 is} selected from the group consisting of hydrogen, hydroxy, A, -OA, C (O) -A and -SO ₂ -A; n is an integer from 0 to 1; Each R ² is independently selected from the group consisting of carboxy, halo, -A, -C (O) -A, -C (O) OA, cyano, -SA, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (C 1 -C 8 -alkyl) and -SO ₂ -N (C 1 -C 8 -alkyl) ₂ ; m is an integer of 0 to 1; Each R ³ is independently selected from the group consisting of -A, -OA, -SA, -NH-A and -C (O) -A; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy, -NH ₂ , -NH (A), -N (A) ₂ , -C (O) NH ₂ , -C (O) -NH (A), -SO ₂ -NH ₂ , -SO ₂ -NH (A) and -OC (O) -A when R ^{4 is} in a β orientation; R ^{4 is} selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, - (C 2 -C 8) -alkynyl-A, (C 2 -C 8) -alkynyl, - (C 2 -C 4) -alkynyl, C8) -alkynyl-A, -OA, -NH ₂ , -NH (A), -N (A) ₂ , -N (A) -C (O) -A, -NH-C (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , -C (O) -NH-A, -SO ₂ -N (A) ₂ , -SO ₂ -NH (A), -SO ₂ -NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O) -A when R ^{4 is} in an α orientation; alternatively, when p is 2, two R ⁴ groups may be taken together as oxo or = N (OH); q is an integer of 0 to 1; R ^{5 is} selected from the group consisting of carboxy, halo, (C 1 -C 4) alkyl and -C (O) -A; wherein the alkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy or (C 1 -C 8) alkoxy; each A is independently selected from the group consisting of (C 1 -C 8) alkyl, aryl, aralkyl, (C 3 -C 8) cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, (C3-C8) -cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy, (C1-C4) -alkyl, ( C 1 -C 8) -alkoxy, nitro, cyano, amino, (C 1 -C 4) -alkylamino or di- ((C 1 -C 4) -alkyl) -amino; or a pharmaceutically acceptable salt thereof. A compound according to claim 2, characterized in that R ^{1 is} selected from the group consisting of hydrogen and -SO ₂ - (C 1 -C 8 alkyl); n is 0; m is 0; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy and -OC (O) - (C 1 -C 8 alkyl); wherein the (C 1 -C 8) -alkyl moiety of the -OC (O) - (C 1 -C 8 -alkyl) group is optionally substituted with a carboxy group; alternatively, when p is 2, two R ⁴ groups are taken together as oxo; q is 0; or a pharmaceutically acceptable salt thereof. A compound according to claim 3, characterized in that R ^{1 is} selected from the group consisting of hydrogen and -SO ₂ -CH ₃ ; n is 0; m is 0; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy and -OC (O) -n-butyl and -OC (O) -CH ₂ CH ₂ CH ₂ CH ₂ -CO ₂ H; alternatively, when p 2, two R ⁴ groups are taken together as oxo; q is 0; or a pharmaceutically acceptable salt thereof. Compound of the formula (II)

wherein R ^{1 is} selected from the group consisting of hydrogen, hydroxy, A, -OA, C (O) -A and -SO ₂ -A; n is an integer from 0 to 2; Each R ² is independently selected from the group consisting of hydroxy, carboxy, halo, -A, -OA, -C (O) -A, -C (O) OA, amino, (C 1 -C 8) alkylamino, di - (C 1 -C 8) -alkylamino, cyano, aminocarbonyl, (C 1 -C 8) -alkylaminocarbonyl, di- (C 1 -C 8) -alkylaminocarbonyl, -SH, -SA, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (C 1 -C 8 -alkyl) and -SO ₂ -N (C 1 -C 8 -alkyl) ₂ ; m is an integer of 0 to 2; Each R ³ is independently selected from the group consisting of -A, -OA, -SA, -NH-A, -N (A) ₂ and -C (O) -A; p is an integer of 1 to 2; Each R ⁴ is independently selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, - (C 2 -C 8) -alkynyl-A, (C 2 -C 8) -alkynyl, (C 2 -C8) alkynyl-A, -OA, -NH ₂ , NH (A), -N (A) ₂ , -N (A) -C (O) -A, -NH-C (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , -C (O) -NH-A, -SO ₂ -N (A) ₂ , -SO ₂ -NH (A), -SO ₂ NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O) -A; alternatively, when p is 2, two R ⁴ groups may be taken together as oxo or = N (OH); q is an integer from 0 to 2; Each R ⁵ is independently selected from the group consisting of hydroxy, carboxy, halo, (C 1 -C 8) alkyl, (C 1 -C 8) alkoxy, (C 3 -C 8) cycloalkyl, and -C (O) -A; wherein the (C 1 -C 8) alkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy or (C 1 -C 8) alkoxy; each A is independently selected from the group consisting of (C 1 -C 8) alkyl, aryl, aralkyl, (C 3 -C 8) cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, (C3-C8) -cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one or more substituents independently selected from halogen, hydroxy, carboxy, (C1-C4) -alkyl, ( C 1 -C 8) -alkoxy, nitro, cyano, amino, (C 1 -C 4) -alkylamino or di- ((C 1 -C 4) -alkyl) -amino; wherein a heteroaryl is a five- or six-membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- or ten-membered bicyclic aromatic ring structure containing at least one heteroatom, which is selected from the group consisting of O, N and S, a heterocycloalkyl is a five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, or a nine- to ten-membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, and an aryl is a carbocyclic aromatic group; or a pharmaceutically acceptable salt thereof. A compound according to claim 5, characterized in that R ^{1 is} selected from the group consisting of hydrogen, hydroxy, A, -OA, C (O) -A and -SO ₂ -A; n is an integer from 0 to 1; Each R ² is independently selected from the group consisting of carboxy, halo, -A, -C (O) -A, -C (O) OA, cyano, -SO-A, -SO ₂ -A, -SO ₂ -NH ₂ , -SO ₂ -NH (C 1 -C 8 -alkyl) and -SO ₂ -N (C 1 -C 8 -alkyl) ₂ ; m is an integer of 0 to 1; Each R ³ is independently selected from the group consisting of -A, -OA, -SA, -NH-A and -C (O) -A; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy, -NH ₂ , -NH (A), -N (A) ₂ , -C (O) NH ₂ , -C (O) -NH (A), -SO ₂ -NH ₂ , -SO ₂ -NH (A) and -OC (O) -A when R ^{4 is} in a β orientation; R ^{4 is} selected from the group consisting of hydroxy, carboxy, cyano, -A, (C 2 -C 8) -alkenyl, - (C 2 -C 8) -alkynyl-A, (C 2 -C 8) -alkynyl, - (C 2 -C 4) -alkynyl, C8) -alkynyl-A, -OA, -NH ₂ , -NH (A), -N (A) ₂ , -N (A) -C (O) -A, -NH-C (O) -A, -C (O) -N (A) ₂ , -C (O) -NH ₂ , -C (O) -NH-A, -SO ₂ -N (A) ₂ , -SO ₂ -NH (A), -SO ₂ -NH ₂ , -N (A) -SO ₂ -A, -NH-SO ₂ -A, -C (O) OA, -OC (O) H and -OC (O) -A when R ^{4 is} in an α orientation; alternatively, when p is 2, two R ⁴ groups may be taken together as oxo or = N (OH); q is an integer of 0 to 1; R ^{5 is} selected from the group consisting of carboxy, halo, (C 1 -C 4) alkyl and -C (O) -A; wherein the alkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy or (C 1 -C 8) alkoxy; each A is independently selected from the group consisting of (C 1 -C 8) alkyl, aryl, aralkyl, (C 3 -C 8) cycloalkyl, heteroaryl and heterocycloalkyl; wherein the aryl, aralkyl, (C3-C8) -cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy, (C1-C4) -alkyl, ( C 1 -C 8) -alkoxy, nitro, cyano, amino, (C 1 -C 4) -alkylamino or di- ((C 1 -C 4) -alkyl) -amino; or a pharmaceutically acceptable salt thereof. A compound according to claim 6, characterized in that R ^{1 is} selected from the group consisting of hydrogen and -SO ₂ - (C 1 -C 8 alkyl); n is an integer from 0 to 1; R ^{2 is} selected from the group consisting of -S- (C 1 -C 8 alkyl); m is 0; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy, (C 2 -C 8) alkynyl, and -OC (O) - (C 1 -C 8 alkyl); alternatively, when p is 2, two R ⁴ groups are taken together as oxo; q is 0; or a pharmaceutically acceptable salt thereof. A compound according to claim 7, characterized in that R ^{1 is} selected from the group consisting of hydrogen and -SO ₂ -CH ₃ ; n is an integer from 0 to 1; R ^{2 is} -S-CH ₃ ; m is 0; p is an integer of 1 to 2; R ^{4 is} selected from the group consisting of hydroxy, ethynyl, and -OC (O) -n-butyl; alternatively, when p 2, two R ⁴ groups are taken together as oxo; q is 0; or a pharmaceutically acceptable salt thereof. Pharmaceutical composition containing a pharmaceutical acceptable carrier and a compound according to claim 1 or claim 5. Pharmaceutical composition produced by Mixing a compound according to claim 1 or claim 5 and a pharmaceutically acceptable carrier. Process for the preparation of a pharmaceutical A composition which comprises mixing a compound according to claim 1 or claim 5 and a pharmaceutically acceptable carrier includes. A compound according to claim 1 or claim 5 for use in therapy. Use of a compound according to claim 1 or Claim 5 for the preparation of a medicament for the treatment of a disorder which is mediated by an estrogen receptor. Use according to claim 13, characterized in that the disorder caused by an Estro gene receptor selected from the group consisting of hot flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia, loss of cognitive function, degenerative brain diseases, cardiovascular diseases, cerebrovascular diseases, breast cancer, hyperplasia of breast tissue, cancer of the endometrium, Uterine lining hyperplasia, cervix cancer, cervical hyperplasia, prostate cancer, benign prostatic hyperplasia, endometriosis, uterine fibroids, osteoarthritis and contraception. Use according to claim 14, characterized that the disorder which is mediated by an estrogen receptor is selected from the group consisting of osteoporosis, hot flashes, vaginal Dryness, breast cancer and endometriosis. Pharmaceutical composition according to claim 10 for use in therapy. Use of a pharmaceutical composition according to claim 10 for the preparation of a medicament for the treatment a fault, by an estrogen receptor is mediated.